Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor)

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Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) Empty Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor)

Post by Cr6 on Sat Feb 25, 2017 11:08 pm

Found these articles intriguing.

Dr. med. Heinrich Kremer (Barcelona 2004)
The secret of cancer: "short-circuit" in the photon switch
Change in the medical world-view of tumorology - The rational Cell Symbiosis Therapy concept

According to Wikipedia, dichloroacetate decreases lactate production by shifting the metabolism of pyruvate from glycolysis towards oxidation in the mitochondria. That is the reason the substance has been used to treat lactic acidosis. Its use in cancer has only recently been pioneered and the University of Alberta researchers caution that more trials are needed, before DCA can be recommended as an anti-tumor agent.

It is against this background that we should see the discovery of Heinrich Kremer, MD, a German medical doctor who is perhaps best known for his unconventional views on AIDS. Kremer says that the current view, according to which the mitochondria's normal energy production pathway is based on chemical oxidation does not go deep enough to allow an understanding of the underlying mechanisms of cancer.

Kremer's discovery is described in his book The Silent Revolution in Cancer and AIDS, which is available here in English: and here in Italian. (site is dead - Cr6)

The new view on cancer is explained in detail in an article titled The Secret of Cancer: Short-circuit in the Photon Switch, due for publication shortly. I will link it here as soon as it becomes available. Meanwhile, here is a sneak preview.

- - -

Cancer and ATP: The Photon Energy Pathway

(for the full article, we must await publication in the July issue of Townsend Letter for Doctors)

Although the mutation theory of oncogenesis is generally accepted today, it does not explain how cancer cells seemingly are able to evade all the body's normal mechanisms that prevent and correct such mutations, and how they can invade and metastasize in different tissues from those that are primarily concerned.

Consequently, our standard therapies, which are based on the assumption that the deviated cells must be destroyed and which attempt to do so by a slash, burn and poison approach operated by the surgeon, the radiologist and the oncologist, are of little use in prolonging the patient's life or effecting real cures.


To understand the new concept of oncogenesis, we must take a look at the evolution of cells and organisms. Cells as present in today's organisms are the result of a fusion, in prehistoric times, of two different types of unicellular life forms into a unique symbiotic combination. A type of cell of the archaea family and another type of the bacteria family entered into symbiosis and formed what is now known as a protist. The cells of mammals including humans today contain genes from both original families. The bacterial symbionts have evolved into the mitochondria which are delegated to take care of energy production.

ATP Energy Pathways

In cancer, the bacterial symbionts go on strike - they refuse to produce any more of the ATP energy molecules they are normally busy churning out all day. The cells thus have to revert to an alternate mode of energy production (glycolysis) which involves fermentation of sugars. This is very much more inefficient than the normal cellular energy mechanism.

But more importantly, and here comes Kremer's very interesting discovery, the normal mode of energy production is not a pure chemical energy pathway. ATP (adenosine triphosphate) is made up of three molecule groups. A base adenine ring that absorbs light quanta in the near ultraviolet band of 270 nanometer wavelength, one sugar molecule and a molecular string with three phosphate groups.

The currently accepted view is that energy production and storage in ATP is by means of chemical energy, stored in the phosphate bonds. The bond energy is then released by hydrolysis in the cytoplasm, where it is used to drive energetic and metabolic processes. Not so, says Kremer. Hydrolysis only yields heat energy, which is not sufficient to drive all the various cell processes. The secret lies in the adenine groups of ATP which absorb photons, but the role of adenine is not adequately explained in the prevailing hypothesis.

The essential components of mitochondrial cell respiration are light absorbing molecules that react to frequencies from the near ultraviolet band down to the yellow/orange spectral range of visible light. Yet, the source of energy for these cellular power plants is not sunlight, as one might easily be led to assume. The flow of para-magnetically aligned electrons in the respiratory organelles gives rise to a low frequency pulsating electromagnetic field which, enormously accelerated through catalytic processes activated by enzymes, in turn activates a spin-mediated information and energy transfer from the physical vacuum, the zero point field, to the biological entity. Consequently, the human organism isn't governed by heat transfer but by a light frequency modulated energy transformation from space background or physical vacuum to the living organism.

Cancer is a result of the disturbance of the enzyme mediated transformation of that energy. The affected cells lose their ability to communicate with other cells around them and they change not only their way of making energy but they become - for all practical purposes - separate unicellular entities that must divide and form a colony to survive. That colony is what we then see as the tumor, the visible manifestation of cancer.

The exact mechanism of that transformation and how the disturbance, once active, feeds back to cause these changes in the cancer cells, is explained - it is a rather technical subject - in Kremer's paper. We will have to wait for its publication to get the whole story.


In the meantime, however, we can say that curcumin, a natural substance in the family of polyphenols contained in turmeric root or curcuma longa and used as a natural coloring agent and a spice, has been found to be beneficial to cancer patients in research at the Anderson Cancer Research Center. See Can a Common Spice Be Used to Treat Cancer?.

Kremer explains that the anti-cancer properties of curcumin are a consequence of its ability to absorb photons in the violet spectral range of visible light at a wavelength of 415 nanometers. This particular property of the healthy spice is what enables it to bridge the broken pathway of photonic energy production and information transfer, thus bringing the affected cells back into the fold, to make them once more function as parts of the organism.

While, admittedly, more research is needed, the pioneering efforts of Kremer will go a long way to point us in the right direction. I hope I was able to stimulate some interest in that new discovery and that you, my readers, are as eagerly awaiting publication of Kremer's research article and book in English as I am.

Watch here for links as soon as they become available.

Meanwhile, there is news that microwaves - as used in mobile telephony - drastically increase the risk of certain cancers. See Cancer Risks from Microwaves Confirmed.


The metabolic advantage of tumor cells

Maurice Israël1Email author and Laurent Schwartz2

Molecular Cancer


©️ Israël and Schwartz; licensee BioMed Central Ltd. 2011
Received: 7 March 2011
Accepted: 7 June 2011
Published: 7 June 2011


1-Oncogenes express proteins of "Tyrosine kinase receptor pathways", a receptor family including insulin or IGF-Growth Hormone receptors. Other oncogenes alter the PP2A phosphatase brake over these kinases.
2-Experiments on pancreatectomized animals; treated with pure insulin or total pancreatic extracts, showed that choline in the extract, preserved them from hepatomas.
Since choline is a methyle donor, and since methylation regulates PP2A, the choline protection may result from PP2A methylation, which then attenuates kinases.
3-Moreover, kinases activated by the boosted signaling pathway inactivate pyruvate kinase and pyruvate dehydrogenase. In addition, demethylated PP2A would no longer dephosphorylate these enzymes. A "bottleneck" between glycolysis and the oxidative-citrate cycle interrupts the glycolytic pyruvate supply now provided via proteolysis and alanine transamination. This pyruvate forms lactate (Warburg effect) and NAD+ for glycolysis. Lipolysis and fatty acids provide acetyl CoA; the citrate condensation increases, unusual oxaloacetate sources are available. ATP citrate lyase follows, supporting aberrant transaminations with glutaminolysis and tumor lipogenesis. Truncated urea cycles, increased polyamine synthesis, consume the methyl donor SAM favoring carcinogenesis.
4-The decrease of butyrate, a histone deacetylase inhibitor, elicits epigenic changes (PETEN, P53, IGFBP decrease; hexokinase, fetal-genes-M2, increase)
5-IGFBP stops binding the IGF - IGFR complex, it is perhaps no longer inherited by a single mitotic daughter cell; leading to two daughter cells with a mitotic capability.
6-An excess of IGF induces a decrease of the major histocompatibility complex MHC1, Natural killer lymphocytes should eliminate such cells that start the tumor, unless the fever prostaglandin PGE2 or inflammation, inhibit them...

The Figure 1 shows how tumors bypass the PK and PDH bottlenecks and evidently, the increase of glucose influx above the bottleneck, favors the supply of substrates to the pentose shunt, as pentose is needed for synthesizing ribonucleotides, RNA and DNA. The Figure 1 represents the stop below the citrate condensation. Hence, citrate quits the mitochondria to give via ATP citrate lyase, acetyl CoA and OAA in the cytosol of tumor cells. Acetyl CoA supports the synthesis of fatty acids and the formation of triglycerides. The other product of the ATP citrate lyase reaction, OAA, drives the transaminase cascade (ALAT and GOT transaminases) in a direction that consumes GLU and glutamine and converts in fine alanine into pyruvate and lactate plus NAD+. This consumes protein body stores that provide amino acids and much alanine (like in starvation). The Figure 1 indicates that malate dehydrogenase is a source of NAD+ converting OAA into malate, which backs-up LDH. Part of the malate converts to pyruvate (malic enzyme) and processed by LDH. Moreover, malate enters in mitochondria via the shuttle and gives back OAA to feed the citrate condensation. Glutamine will also provide amino groups for the "de novo" synthesis of purine and pyrimidine bases particularly needed by tumor cells. The Figure 1 indicates that ASP shuttled out of the mitochondrial, joins the ASP formed by cytosolic transaminases, to feed the synthesis of pyrimidine bases via ASP transcarbamylase, a process also enhanced in tumor cells. In tumors, this silences the argininosuccinate synthetase step of the urea cycle [18–20]. This blockade also limits the supply of fumarate to the Krebs cycle. The latter, utilizes the α ketoglutarate provided by the transaminase reaction, since α ketoglutarate coming via aconitase slows down. Indeed, NO and peroxynitrite increase in tumors and probably block aconitase. The Figure 1 indicates the cleavage of arginine into urea and ornithine. In tumors, the ornithine production increases, following the polyamine pathway. Ornithine is decarboxylated into putrescine by ornithine decarboxylase, then it captures the backbone of S adenosyl methionine (SAM) to form polyamines spermine then spermidine, the enzyme controlling the process is SAM decarboxylase. The other reaction product, 5-methlthioribose is then decomposed into methylthioribose and adenine, providing purine bases to the tumor. We shall analyze below the role of SAM in the carcinogenic mechanism, its destruction aggravates the process.

Figure 1

Cancer metabolism. Glycolysis is elevated in tumors, but a pyruvate kinase (PK) "bottleneck" interrupts phosphoenol pyruvate (PEP) to pyruvate conversion. Thus, alanine following muscle proteolysis transaminates to pyruvate, feeding lactate dehydrogenase, converting pyruvate to lactate, (Warburg effect) and NAD+ required for glycolysis. Cytosolic malate dehydrogenase also provides NAD+ (in OAA to MAL direction). Malate moves through the shuttle giving back OAA in the mitochondria. Below the PK-bottleneck, pyruvate dehydrogenase (PDH) is phosphorylated (second bottleneck). However, citrate condensation increases: acetyl-CoA, will thus come from fatty acids β-oxydation and lipolysis, while OAA sources are via PEP carboxy kinase, and malate dehydrogenase, (pyruvate carboxylase is inactive). Citrate quits the mitochondria, (note interrupted Krebs cycle). In the cytosol, ATPcitrate lyase cleaves citrate into acetyl CoA and OAA. Acetyl CoA will make fatty acids-triglycerides. Above all, OAA pushes transaminases in a direction usually associated to gluconeogenesis! This consumes protein stores, providing alanine (ALA); like glutamine, it is essential for tumors. The transaminases output is aspartate (ASP) it joins with ASP from the shuttle and feeds ASP transcarbamylase, starting pyrimidine synthesis. ASP in not processed by argininosuccinate synthetase, which is blocked, interrupting the urea cycle. Arginine gives ornithine via arginase, ornithine is decarboxylated into putrescine by ornithine decarboxylase. Putrescine and SAM form polyamines (spermine spermidine) via SAM decarboxylase. The other product 5-methylthioadenosine provides adenine. Arginine deprivation should affect tumors. The SAM destruction impairs methylations, particularly of PP2A, removing the "signaling kinase brake", PP2A also fails to dephosphorylate PK and PDH, forming the "bottlenecks". (Black arrows = interrupted pathways).

In summary, it is like if the mechanism switching from gluconeogenesis to glycolysis was jammed in tumors, PK and PDH are at rest, like for gluconeogenesis, but citrate synthase is on. Thus, citric acid condensation pulls the glucose flux in the glycolytic direction, which needs NAD+; it will come from the pyruvate to lactate conversion by lactate dehydrogenase (LDH) no longer in competition with a quiescent Pcarb. Since the citrate condensation consumes acetyl CoA, ketone bodies do not form; while citrate will support the synthesis of triglycerides via ATP citrate lyase and fatty acid synthesis... The cytosolic OAA drives the transaminases in a direction consuming amino acid. The result of these metabolic changes is that tumors burn glucose while consuming muscle protein and lipid stores of the organism. In a normal physiological situation, one mobilizes stores for making glucose or ketone bodies, but not while burning glucose! Tumor cell metabolism gives them a selective advantage over normal cells. However, one may attack some vulnerable points.

Last edited by Cr6 on Sat Mar 31, 2018 1:59 am; edited 1 time in total


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Post by Cr6 on Sat Feb 25, 2017 11:58 pm

He mentions of few things like "zero-point"... hmm. Mentions also a Photon Switch.

Biochemistry and medical science have failed to this day to explain the function of the adenine groups of ATP as no biochemical reaction with this adenine ring molecule is shown. However, an understanding can be gained, within the framework of the cell symbiosis concept, from the biophysical attributes of light absorption of the adenine group. All essential components of mitochondrial cell respiration are light absorbing molecules with characteristic "frequency windows" of absorption maxima from nearly UV spectrum to the longer wave yellow/orange spectral range of visible light up to ca. 600nm. Yet the source of the electromagnetic energy is not sunlight. In fact a low frequency pulsating electromagnetic field is induced by the constant flow of uncoupled, paramagnetic aligned electrons in the respiratory organelles. The electromotive power generated by this process is catalytically enormously strengthened by the enzyme complexes of the respiratory chain (acceleration factor1017). .

This effects an interaction between the electrons and the protons likewise aligned parallel to the induced magnetic field dependent on the strength of the magnetic field between the antiparallel aligned electrons and protons. This process produces a quantum dynamic transfer of information via photon exchange energy. The source of photons is ultimately fluctuations of resonance frequencies of the physical vacuum (zero-point energy field). The transferred information is stored in the spin of the protons that proceed to the ATP synthesis complex via proton gradients. There the resonance information is transferred by a unique rotation system to the adenine group of ATP whose electrons can move freely in the alternating double bonds of the ring molecules. The ATP serves as an "antennae molecule" for the reception and relaying of resonance information from the "morphogenetic background field." Human symbiosis is consequently not a heat power machine but a light frequency modulated information transforming medium. All the time this cell symbiosis is resonance coupled with the lowest not yet materialized energy status (physical vacuum as inexhaustible "global information pool").

   In oncogenesis, for a diversity of reasons, there is a functional disturbance especially to the 4th enzyme complex of the respiratory chain. The task of this complex, according to conventional opinions, is to transfer the inflowing electrons to molecular oxygen at the end of the respiratory chain and thus reduce it to water. In the cell symbiosis concept, however, the crucial factor is that in reducing O2 to water completed electron couplings induce an antimagnetic impulse, and the electromagnetic alternating field for resonance information transfer switches on and off at an extremely fast periodic time interval (in picoseconds). If the electron flows to O2 , however, are permanently disturbed then a failure in the modulation of ATP occurs and increasing numbers of oxygen and other radicals form that can attack and damage the macromolecules (nucleic acids, proteins, lipids, carbohydrates). In order to prevent this danger the key enzyme hemoxygenase upregulates. This enzyme uses O2  as cofactor for the production of carbon monoxide (CO). In cases of long-term surplus production CO gas has crucial effects on cancer cell transformation:

-CO gas effects a characteristic phase shifting of the absorption of visible light from components of the respiratory chain and as a result "short-circuits" the photon switch for the modulation of the information transfer to the mitochondrial ATP

-CO gas activates in the cytoplasm certain regulator proteins for the stimulation of the cell division cycle also without external growth signals (see above: 1st "acquired capability")

-CO gas effects via enzymatic overactivation of the important secondary messenger substance cyclic guanosin monophosphate (cGMP) the inhibition or blockade of communication between neighboring cells (2nd "acquired capability" of cancer cells)

-CO gas blocks programmed cell death by bonding onto the bivalent iron in important key enzymes (3rd "acquired capability" of cancer cells)

The result is a polar program reversal: The transformed cancer cells remain trapped, dependent on the degree of malignancy, in a continuous cell division cycle and can not switch back to the differentiated cell performances of the respective cell types without biological compensatory aid. According to recent clinical knowledge the cancer cells become especially malign and disperse massive metastatic cells when the O2 supply to tumor cells via capillary blood vessels is impeded. In these cases chemotherapy and radiation treatment are no longer effective as without the presence of molecular oxygen programmed cell death of the cancer cells can no longer be induced. In this situation cancer patients are considered incurable by oncologists using standard cancer therapy.

In 2003, American cancer researchers confirmed a functional disruption of cancer cells in the 4th complex of the respiratory chain despite simultaneously intact messenger RNA and intact mitochondrial DNA, without being able to explain this phenomenon. However, at the end of 2002 a cancer research group from Helsinki University, after many years of animal experiments and clinical studies, were able to exactly document for the first time - using electronmicroscopes and mass spectrometers – that the transformation to cancer cells is actually caused by the loss of control of the cell division cycle of the mitochondria. The clinical research team could demonstrate that the tumor cells after a relatively short time had re-programmed to intact, normal differentiated cells without signs of programmed cell death by using a particular experimentally mediated bioimmunological compensation therapy on various human cancer diseases. These patients under conventional tumor therapy had a survival status of on average less than 12 months. In 2003 researchers from the Anderson Cancer Research Center of the University of Texas in Houston published the first wide-ranging overview about the hundreds of animal experiments on the effects of curcumin, the active ingredient of turmeric (Curcuma Longa, from the ginger family, biochemically, curcumin I from the molecular family of polyphenols, also termed bioflavonoids, synthesized from plants) on cancer cells and metastases. The researchers were amazed to discover that curcumin effectively inhibited nearly all signal paths in tumor cells and metastases. The researchers were unable to provide an explanation to this wide-ranging effect. The actions of curcumin can, however, be explained if you know that curcumin in the violet spectral range of visible light absorbs with nearly the same wavelength - 415 nm - as the electron-transferring molecule cytochrome c that is more rapidly broken up by the protective enzyme hemoxygenase in cancer cells. In cancer cells curcumin, so to say, bridges the III and IV complex photon switch “short-circuit” of the respiratory chain in mitochondria and thus normalizes the information transfer for maintaining modulation of ATP. The quoted research data show that (in opposition to the prevailing cancer theories of supposedly irreparable gene defects in the nucleus) the demonstrated functional disruptions of the transfer of information in cell symbionts can be re-normalized by means of an adequate biological compensation therapy. The concept of cell symbiosis therapy (Kremer 2001) derived from knowledge gained from cell symbiosis research has in the meantime led to spectacular therapeutic successes (in individual cases even in cancer diseases that had been declared incurable). There is a broad spectrum of classes of substances responding to natural light available and the potential is by no means exhausted. What is desperately needed, however, is a comprehensive overhaul of the current state of research with the aim of developing optimized therapeutic formulations and to make them available for clinical and therapeutic practice. Admittedly, achieving this purpose through an interdisciplinary research group within the established health system is not to be expected in the foreseeable future, as conventional medical science has largely remained stuck in the one-sided thermodynamic energy concepts of the 19th Century.


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Post by Jared Magneson on Wed Mar 08, 2017 4:52 am

The flow of para-magnetically aligned electrons in the respiratory organelles gives rise to a low frequency pulsating electromagnetic field which, enormously accelerated through catalytic processes activated by enzymes, in turn activates a spin-mediated information and energy transfer from the physical vacuum, the zero point field, to the biological entity. Consequently, the human organism isn't governed by heat transfer but by a light frequency modulated energy transformation from space background or physical vacuum to the living organism.

There is no zero-point energy or borrowing from the vacuum. We can assume all charge input is based on Mathis's principles and theories, since he's the only one so far who's ever really proposed or outlined them. Even the cells themselves experience charge recycling.

Jared Magneson

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Post by Cr6 on Sun Mar 11, 2018 4:06 am

Researchers develop new dichloroacetate formulation for cancer treatment
April 16, 2014 by Jessica Luton, University of Georgia

Shanta Dhar, right, and Sean Marrache

Health forums were abuzz in 2007 with news that a simple, inexpensive chemical may serve as a viable treatment to many forms of cancer. The drug dichloroacetate, or DCA, was touted as a cure-all, but after years of work, scientists are still searching for ways to make the unique treatment as effective as possible.

Now, researchers at the University of Georgia have discovered a new way to deliver this drug that may one day make it a viable treatment for numerous forms of cancer. They published their findings in the American Chemical Society's journal ACS Chemical Biology.

"DCA shows great promise as a potential cancer treatment, but the drug doesn't find and attack cancer cells very efficiently in the doses researchers are testing," said Shanta Dhar, an assistant professor of chemistry in the UGA Franklin College of Arts and Sciences. "We have developed a new compound based on DCA that is three orders of magnitude more potent than standard treatments."

Every cell in the body needs energy to divide and grow, and most of them do this by breaking down sugar. When cells misbehave, they are normally deprived of their food and die in a process called apoptosis.

Cancerous cells, however, find a way around the natural order by discovering other sources of energy. Dhar's technology, which she calls Mito-DCA, destroys the cancer by focusing on a part of the cell called mitochondria, commonly known as the powerhouse of cells because they generate most of the cell's chemical energy.

"By targeting the mitochondria, we can force cancerous cells to die just as regular malfunctioning cells would," said Dhar, who is part of the UGA Cancer Center. "But the drug we have developed affects only cancerous cells, leaving normal cells undisturbed."

In their experiments, Dhar and her research team exposed cancer cells to Mito-DCA. The results showed that the engineered chemical substance was able to switch the glycolysis-based metabolism of cancer cells to glucose oxidation, meaning that the cancer cells can once again die via apoptosis.

Mito-DCA also suppressed the production of lactic acid in cancerous cells, which allows them to avoid detection by the body's immune system. With this cloaking device damaged, the body's own T-cells are better able to recognize tumors and eliminate them. (more at link...)


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Post by Cr6 on Sun Mar 11, 2018 6:02 pm

Overview of DCA:

Canadian Martin Winer on DCA with two Doctors and their research findings:


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Post by Cr6 on Wed Mar 14, 2018 1:59 am

Don't mean to overpost on this topic but these are some related links with DCA and ATP/Glucose/Glycosis/Warburg Effect/mitochondria activity:

In another study, the researchers explain that cancer cells initiate a "lactate shuttle" to move lactate -- the "food" -- from the connective tissue to the cancer cells. There's a transporter that is "spilling" lactate from the connective tissue and a transporter that then "gobbles" it up in the cancer cells."

▪️ The implication is that the fibroblasts in the connective tissue are feeding cancer cells directly via pumps, called MCT1 and MCT4, or mono-carboxylate transporters. The researchers see that lactate is like "candy" for cancer cells. And cancer cells are addicted to this supply of "candy."

▪️ "We've essentially shown for the first time that there is lactate shuttle in human tumors," said Dr. Lisanti. "It was first discovered nearly 100 years ago in muscles, 15 years ago in the brain, and now we've shown this shuttle also exists in human tumors."
▪️ It's all the same mechanism, where one cell type literally "feeds" the other. The cancer cells are the "Queen Bees," and the connective tissue cells are the "Worker Bees." In this analogy, the "Queen Bees" use aging and inflammation as the signal to tell the "Worker Bees" to make more food.
▪️ Researchers also identified MCT4 as a biomarker for oxidative stress in cancer-associated fibroblasts, and inhibiting it could be a powerful new anti-cancer therapy.
▪️ "If lethal cancer is a disease of "accelerated aging" in the tumor's connective tissue, then cancer patients may benefit from therapy with strong antioxidants and anti-inflammatory drugs," said Dr. Lisanti. "Antioxidant therapy will "cut off the fuel supply" for cancer cells." Antioxidants also have a natural anti-inflammatory action.
The energetic requirements of a body are composed of the basal metabolic rate and the physical activity level. This caloric requirement can be met with protein, fat, carbohydrates, alcohol, or a mixture of those. Glucose is the general metabolic fuel, and can be metabolized by any cell. Fructose and some other nutrients can only be metabolized in the liver, where their metabolites transform into either glucose stored as glycogen in the liver and in muscles, or into fatty acids stored in adipose tissue.
Simple sugar, lactate, is like 'candy for cancer cells': Cancer cells accelerate aging and inflammation in the body to drive tumor growth

Related article with big claims from many years back.

Ancient remedy? An extract from the wormwood plant kills breast cancer cells in a test tube.
Wormwood Extract Kills Cancer Cells

By Deborah HillNov. 30, 2001 , 12:00 AM

Medieval as it sounds, scientists are testing a recipe of wormwood and iron on breast cancer cells, and so far the results are encouraging. In a new study, researchers report that artemesinin--a derivative of the wormwood plant--kills iron-enriched breast cancer cells but doesn't harm many healthy ones. Artemesinin's destructive properties are triggered by higher than normal levels of iron in cancer cells.

Many experiments have found that artemesinin turns deadly in the presence of iron. In Asia and Africa, artemesinin tablets are widely and, in many cases, successfully used to treat malaria, because the parasite has a high iron concentration. Cancer cells can also be rich in iron, as they often soak up the mineral to facilitate cell division. The cells bring in extra iron with the help of transferrin receptors, special receiving points that funnel the mineral into the cell. Although normal cells also have transferrin receptors, cancerous ones can have many more.

Lactic Acidosis as a Result of Iron Deficiency
Clement A. Finch, Philip D. Gollnick, Michael P. Hlastala, Louise R. Miller, Erick Dillmann, and Bruce Mackler

First published July 1, 1979 - More info
It is concluded that iron deficiency by a depletion in the iron-containing mitochondrial enzyme, α-glycerophosphate oxidase, impairs glycolysis, resulting in excess lactate formation, which at high levels leads to cessation of physical activity.

The Glycogen Shunt Maintains Glycolytic Homeostasis and the Warburg Effect in Cancer
Robert G. Shulman, Douglas L. Rothman'Correspondence information about the author Douglas L. Rothman

The Glycogen Shunt Maintains Glycolytic Homeostasis and the Warburg Effect in Cancer
DOI: |

Under aerobic conditions cancer cells consume more glucose than they oxidize for energy, a phenomenon known as the Warburg effect.

There have been many proposed critical functions for the Warburg effect in cancer cells, but none have been definitively shown.

The glycogen shunt has been recently shown to be essential for cancer cell survival.

The critical role of the glycogen shunt in maintaining metabolic homeostasis, recently shown in yeast, provides a novel explanation and mechanism for its importance in cancer cells and the Warburg effect.

Despite many decades of study there is a lack of a quantitative explanation for the Warburg effect in cancer. We propose that the glycogen shunt, a pathway recently shown to be critical for cancer cell survival, may explain the excess lactate generation under aerobic conditions characteristic of the Warburg effect. The proposal is based on research on yeast and mammalian muscle and brain that demonstrates that the glycogen shunt functions to maintain homeostasis of glycolytic intermediates and ATP during large shifts in glucose supply or demand. Loss of the glycogen shunt leads to cell death under substrate stress. Similarities between the glycogen shunt in yeast and cancer cells lead us here to propose a parallel explanation of the lactate produced by cancer cells in the Warburg effect. The model also explains the need for the active tetramer and inactive dimer forms of pyruvate kinase (PKM2) in cancer cells, similar to the two forms of Pyk2p in yeast, as critical for regulating the glycogen shunt flux. The novel role proposed for the glycogen shunt implicates the high activities of glycogen synthase and fructose bisphosphatase in tumors as potential targets for therapy.

To test artemesinin's effect on breast cancer cells, bioengineers Henry Lai and Narendra Singh of the University of Washington, Seattle, enriched segregated normal breast cells and radiation-resistant cancerous ones with holotransferrin, a compound normally found in the body that carries iron to the cells. Then the team dosed the cells with artemesinin. As the pair reports in the 16 November issue of Life Sciences, almost all the cancer cells exposed to holotransferrin and artemesinin died within 16 hours. The compounds killed only a few of the normal cells. Lai believes that because a breast cancer cell contains five to 15 more receptors than normal, it absorbs iron more readily and hence is more susceptible to artemesinin's attack.

"This looks very promising," says Gary Poser, an organic chemist at Johns Hopkins University in Baltimore, Maryland. Still, he adds, "other researchers need to replicate these results." The next step, says Poser, is to treat a mixture of normal and cancerous cells, instead of segregating the two. Lai and others are also interested in artemesinin's effect on other cancers.

Duke scientists show why cells starved of iron burn more glucose
Duke University Medical Center

The first response to iron deficiency is to shut down the energy hub of the cell, the mitochondria, which takes glucose and turns it efficiently into cell energy fuel, or ATP. The mitochondria depend greatly on iron. As a cell becomes more starved for iron, it "dials down" the mitochondrial processes by degrading the mRNAs encoding the proteins involved in such processes, and thus, some iron is freed up, Thiele said.

The second response is to shut down iron storage pathways and other, more dispensable biochemical reactions that depend on iron. "When you are low on iron, you don't want to save it and take it out of use," Thiele explained.

The third response is to increase glucose utilization pathways outside of the mitochondria, which is a much less efficient way to produce energy. Glucose molecules processed for energy outside of the mitochondria create about 18 times less energy, said co-author Sandra Vergara, a doctoral student in Thiele's lab.

"Cellular iron balance follows the rules of economics," Vergara said. "During scarcity, the cell prioritizes the utilization of iron, saving it for more essential processes. This prioritization comes at a cellular cost, which is reflected in the higher demand for glucose, so the cell can keep the correct amount of energy flowing."

If we run low on ATP, we become tired and lethargic, which are symptoms of iron deficiency, Thiele said. "Iron is hard for humans to get from plant sources, which form the basis for most of the world's diet." Iron is very abundant in nature, but cells have a hard time taking it up, because it can change its form inside the body.

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Post by Cr6 on Wed Mar 14, 2018 2:20 am

J Clin Invest. 1987 Feb;79(2):588-94.
Dichloroacetate inhibits glycolysis and augments insulin-stimulated glycogen synthesis in rat muscle.
Clark AS, Mitch WE, Goodman MN, Fagan JM, Goheer MA, Curnow RT.


The decrease in plasma lactate during dichloroacetate (DCA) treatment is attributed to stimulation of lactate oxidation. To determine whether DCA also inhibits lactate production, we measured glucose metabolism in muscles of fed and fasted rats incubated with DCA and insulin. DCA increased glucose-6-phosphate, an allosteric modifier of glycogen synthase, approximately 50% and increased muscle glycogen synthesis and glycogen content greater than 25%. Lactate release fell; inhibition of glycolysis accounted for greater than 80% of the decrease. This was associated with a decrease in intracellular AMP, but no change in citrate or ATP. When lactate oxidation was increased by raising extracellular lactate, glycolysis decreased (r = - 0.91), suggesting that lactate oxidation regulates glycolysis. When muscle lactate production was greatly stimulated by thermal injury, DCA increased glycogen synthesis, normalized glycogen content, and inhibited glycolysis, thereby reducing lactate release. The major effect of DCA on lactate metabolism in muscle is to inhibit glycolysis.


Dichloroacetate Stimulates Glycogen Accumulation in Primary Hepatocytes through an Insulin-Independent Mechanism

Melissa K. Lingohr Richard J. Bull Junko Kato-Weinstein Brian D. Thrall
Toxicological Sciences, Volume 68, Issue 2, 1 August 2002, Pages 508–515,
Published: 01 August 2002


Dichloroacetate (DCA), a by-product of water chlorination, causes liver cancer in B6C3F1 mice. A hallmark response observed in mice exposed to carcinogenic doses of DCA is an accumulation of hepatic glycogen content. To distinguish whether the in vivo glycogenic effect of DCA was dependent on insulin and insulin signaling proteins, experiments were conducted in isolated hepatocytes where insulin concentrations could be controlled. In hepatocytes isolated from male B6C3F1 mice, DCA increased glycogen levels in a dose-related manner, independently of insulin. The accumulation of hepatocellular glycogen induced by DCA was not the result of decreased glycogenolysis, since DCA had no effect on the rate of glucagon-stimulated glycogen breakdown. Glycogen accumulation caused by DCA treatment was not hindered by inhibitors of extracellular-regulated protein kinase kinase (Erk1/2 kinase or MEK) or p70 kDa S6 protein kinase (p70S6K), but was completely blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitors, LY294002 and wortmannin. Similarly, insulin-stimulated glycogen deposition was not influenced by the Erk1/2 kinase inhibitor, PD098509, or the p70S6K inhibitor, rapamycin. Unlike DCA-stimulated glycogen deposition, PI3K-inhibition only partially blocked the glycogenic effect of insulin. DCA did not cause phosphorylation of the downstream PI3K target protein, protein kinase B (PKB/Akt). The phosphorylation of PKB/Akt did not correlate to insulin-stimulated glycogenesis either. Similar to insulin, DCA in the medium decreased IR expression in isolated hepatocytes. The results indicate DCA increases hepatocellular glycogen accumulation through a PI3K-dependent mechanism that does not involve PKB/Akt and is, at least in part, different from the classical insulin-stimulated glycogenesis pathway. Somewhat surprisingly, insulin-stimulated glycogenesis also appears not to involve PKB/Akt in isolated murine hepatocytes.
dichloroacetate, glycogen, insulin, insulin receptor, PKB/Akt, PI3K, hepatocyte

Dichloroacetate (DCA) is a common by-product formed during drinking water chlorination and is hepatocarcinogenic in B6C3F1 mice and F344 rats (Bull et al., 1990; DeAngelo et al., 1991, 1996; Pereira, 1996; Stauber and Bull, 1997). A hallmark effect of DCA treatment in mice is a marked accumulation of hepatocellular glycogen (Bull et al., 1990; Kato-Weinstein et al., 1998). The dose-response relationship for glycogen accumulation in mice closely parallels the dose-response relationship for the carcinogenic effects of DCA (Bull et al., 1990; Kato-Weinstein et al., 1998; Stauber and Bull, 1997). It is not known whether the mechanisms by which DCA causes hepatocellular carcinoma and stimulates hepatocellular glycogen content are related. However, a link between altered glycogen metabolism and liver cancer risk is suggested by the fact that patients with glycogen storage disease have a significantly increased incidence of liver cancer (Alshak et al., 1994; Conti and Kemeny, 1992; Labrune et al., 1997).

Glycogen synthase is the rate-limiting enzyme of glycogen biosynthesis, and its activation is regulated by a reversible dephosphorylation mechanism in which several insulin-controlled phosphatases and kinases can be involved (Pugazenthi and Khandelwal, 1995). The principal signaling pathway by which insulin stimulates glycogen synthase is via activation of the insulin receptor (IR), leading to phosphatidylinositol-3′ kinase (PI3K)-dependent activation of protein kinase B (PKB/Akt), inactivation of glycogen synthase kinase-3 (GSK-3), and increased activity of glycogen synthase (GS) (Cohen, 1999; Cross et al., 1995, 1997; Lawrence and Roach, 1997; Park et al., 1999). PI3K-dependent activation of the p70 kDa S6 protein kinase (p70S6K) as well as activation of the Ras/Raf/MEK/Erk1/2 signaling pathway have also been linked with GSK-3 inactivation and increased glycogen synthesis (Azpiazu et al., 1996; Dent et al., 1990; Park et al., 1999; Shepherd et al., 1995; Sutherland and Cohen, 1994; Sutherland et al., 1993). In addition to their role in regulating metabolism, the activities of PI3K, PKB/Akt and Erk1/2 play important roles in regulating cell proliferation and apoptosis in hepatocytes (reviewed in Band et al., 1999; Galetic et al., 1999; Mounho and Thrall, 1999; Roberts et al., 2000).


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Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) Empty Re: Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor)

Post by Cr6 on Wed Mar 14, 2018 3:11 am

Sugars Increase Non-Heme Iron Bioavailability in Human Epithelial Intestinal and Liver Cells

Tatiana Christides ,Paul Sharp
Published: December 10, 2013


Previous studies have suggested that sugars enhance iron bioavailability, possibly through either chelation or altering the oxidation state of the metal, however, results have been inconclusive. Sugar intake in the last 20 years has increased dramatically, and iron status disorders are significant public health problems worldwide; therefore understanding the nutritional implications of iron-sugar interactions is particularly relevant. In this study we measured the effects of sugars on non-heme iron bioavailability in human intestinal Caco-2 cells and HepG2 hepatoma cells using ferritin formation as a surrogate marker for iron uptake. The effect of sugars on iron oxidation state was examined by measuring ferrous iron formation in different sugar-iron solutions with a ferrozine-based assay. Fructose significantly increased iron-induced ferritin formation in both Caco-2 and HepG2 cells. In addition, high-fructose corn syrup (HFCS-55) increased Caco-2 cell iron-induced ferritin; these effects were negated by the addition of either tannic acid or phytic acid. Fructose combined with FeCl3 increased ferrozine-chelatable ferrous iron levels by approximately 300%. In conclusion, fructose increases iron bioavailability in human intestinal Caco-2 and HepG2 cells. Given the large amount of simple and rapidly digestible sugars in the modern diet their effects on iron bioavailability may have important patho-physiological consequences. Further studies are warranted to characterize these interactions.


Evidence that simple sugars such as glucose and fructose affect iron bioavailability first arose in the 1960s from work showing that sugars were able to chelate inorganic iron and form stable, low molecular weight soluble complexes [1]. These sugar-iron complexes were readily absorbed across the intestinal mucosa of rodent models [2], [3]. Given that intake of fructose and sucrose has increased dramatically worldwide in the past 40 years, especially in the Western world, while at the same time iron deficiency and iron excess remain significant public health concerns [4]–[6], understanding the nutritional implications of iron-sugar interactions is particularly relevant.

Excess sugar is blamed for a myriad of modern health problems, but whether sugars might actually be protective against iron deficiency, or contribute to either total body or cellular iron overload is unknown. Insufficient body iron levels are associated with significant health consequences, and approximately 2 billion people suffer from iron deficiency. Furthermore, iron overload related to either primary (e.g. hereditary hemochromatosis) or secondary (e.g. beta-thalassemia) abnormalities in iron metabolism is prevalent in many populations [6], [7]. There is also interest in the role that disordered regulation of intracellular iron levels plays in the pathogenesis of several non-communicable diseases including non-alcoholic fatty liver disease (NAFLD) [8], [9].

Citation: Christides T, Sharp P (2013) Sugars Increase Non-Heme Iron Bioavailability in Human Epithelial Intestinal and Liver Cells. PLoS ONE 8(12): e83031.


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Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) Empty Re: Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor)

Post by Cr6 on Sun Mar 18, 2018 10:37 pm

Something like Biophoton's are probably in play as well with Cancer.  This is seen as a "pseudo-science" by some researchers. Though, there are Biophotons operating in the brain apparently.


Are There Optical Communication Channels in Our Brains?

Neuroscientists have long observed biophotons produced in brain tissue. Nobody knows what these photons are for, but researchers are beginning to explore the possibilities.

by Emerging Technology from the arXiv September 6, 2017

Here’s an interesting question: are there optical communication channels in the brain? This may be a radical suggestion but one for which there is more than a little evidence to think it is worth pursuing.

Many organisms produce light to communicate, to attract mates, and so on. Twenty years ago, biologists discovered that rat brains also produce photons in certain circumstances. The light is weak and hard to detect, but neuroscientists were surprised to find it at all.

Since then, the evidence has grown. So-called biophotons seem to be produced naturally in the brain and elsewhere by the decay of certain electronically excited molecular species. Mammalian brains produce biophotons with wavelength of between 200 and 1,300 nanometers—in other words, from near infrared to ultraviolet.

Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) Brain-photons
Biophoton Communication: Can Cells Talk Using Light?

(more at link)

A growing body of evidence suggests that the molecular machinery of life emits and absorb photons. Now one biologist has evidence that this light is a new form of cellular communication.

   May 22, 2012

One of the more curious backwaters of biology is the study of biophotons: optical or ultraviolet photons emitted by living cells in a way that is distinct from conventional bioluminescence.

Nobody is quite sure how cells produce biophotons but the latest thinking is that various molecular processes can emit photons and that these are transported to the cell surface by energy carying excitons. A similar process carries the energy from photons across giant protein matrices during photosynthesis.

Whatever the mechanism, a growing number of biologists are convinced that when you switch off the lights, cells are bathed in the pale fireworks of a biophoton display.

This is not a bright phenomena. Biophotons are usually produced at the rate of dozens per second per square centimetre of cell culture.

Ref: Photonic Communications and Information Encoding in Biological Systems
That’s not many. And it’s why the notion that biophoton activity is actually a form of cellular communication is somewhat controversial.    

Today, Sergey Mayburov at the Lebedev Institute of Physics in Moscow adds some extra evidence to the debate.

Mayburov has spent many hours in the dark watching fish eggs and recording the patterns of biophotons that these cells emit.

The question he aims to answer is whether the stream of photons has any discernible structure that would qualify it as a form of communication.

The answer is that is does, he says. Biophoton streams consist of short quasiperiodic bursts, which he says are remarkably similar to those used to send binary data over a noisy channel. That might help explain how cells can detect such low levels of radiation in a noisy environment.

If he’s right, then this could help to explain a number of interesting phenomenon that some biologists attribute to biophoton communication.

In several experiments, biophotons from a growing plant seem to increase the rate of cell division in other plants by 30 per cent. That’s a growth rate that is significantly higher than is possible with ordinary light that is several orders of magnitude more intense.

Other experiments have shown that the biophotons from growing eggs can encourage the growth of other eggs of a similar age. However, the biophotons from mature eggs can hinder and disrupt the growth of younger eggs at a different stage of development. In some cases, biophotons from older eggs seem to stop the growth of immature eggs entirely.

Mayburov’s work won’t end the controversy; not by any means. There are still many outstanding questions. One important problem is to better understand the cellular mechanisms at work–how the molecular machinery inside cells produces photons and how it might be influenced by them.


Are There Optical Communication Channels in Our Brains?
Neuroscientists have long observed biophotons produced in brain tissue. Nobody knows what these photons are for, but researchers are beginning to explore the possibilities.

by Emerging Technology from the arXiv September 6, 2017

Here’s an interesting question: are there optical communication channels in the brain? This may be a radical suggestion but one for which there is more than a little evidence to think it is worth pursuing.


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Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) Empty Re: Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor)

Post by Cr6 on Sun Mar 18, 2018 11:46 pm

Related to "biophotons" and cancer...pretty interesting overall:

Cancer Nanotechnol. 2013; 4(1-3): 21–26.
Published online 2013 March 28. doi:  10.1007/s12645-013-0034-7
PMCID: PMC4451865
Enhancement of biophoton emission of prostate cancer cells by Ag nanoparticles
Marius Hossu, Lun Ma, Xiaoju Zou, and Wei Chen corresponding author


Ultraweak intrinsic bioluminescence of cancer cell is a noninvasive method of assessing bioenergetic status of the investigated cells. This weak biophoton emission generated by prostate cancer cells (PC3) was measured in the presence of Ag nanoparticles and its correlation with singlet oxygen production was investigated. The comparison between nanoparticles concentration, bioluminescence intensity, and cell survival showed that Ag nanoparticles do not significantly affect cell survival at used concentration but they increase cell bioluminescent processes. It was also confirmed that singlet oxygen contributes to biophoton emission, that Ag nanoparticles increase this contribution, and that there are secondary mechanisms independent of singlet oxygen by which Ag nanoparticles contribute to increased cellular bioluminescence, possibly through plasmon resonance enhancement of intrinsic fluorescence.

Keywords: Silver nanoparticle, Bioluminescence, Biophoton, PC3, Cancer, Singlet oxygen, Plasmon resonance


Luminescence investigation is a fundamental tool in cellular biology and a useful method in understanding molecular mechanisms of medical therapies. One of these methods is the measurement of intrinsic bioluminescence of living tissue, process also called biophoton emission (BPE) (Popp et al. 1988; Cohen and Popp 1997; Kobayashi and Inaba 2000; Chang 2008). The advantage of using BPE is that it monitors intrinsic processes of the investigated biological system versus the interaction of the system with an external stimulus, be it light in fluorescence, magnetic field in MRI, X-ray in CT, etc. It was demonstrated that all cells emits light during normal metabolic processes ( Kobayashi and Inaba 2000; Chang 2008). However, due to its extremely low intensity and its sensitivity to interaction with ambient light, this intrinsic bioluminescence was rarely used as a monitoring tool for cells’ physiology or pathology. The typical light emission is in the order of tens of photons per second per square centimeter of tissue hence the term biophoton is used more often and only very sensitive and very low noise phototomultipliers are used to record it. One of the emission’s mechanisms was correlated with the generation of metastable excited states by high energetic metabolic processes (cellular respiration, phagocytosis, mitosis, neural activity) and by oxidative reactions (Cilento 1988; Villablanca and Cilento 1985; Devaraj et al. 1997; Van Wijk et al. 2008). Most common identified excited molecules are intrinsic fluorophores, singlet oxygen, or excited carbonil (Villablanca and Cilento 1985). Other suggested sources are excitons in macromolecules, particularly DNA and collagen ( Popp et al. 1984; Brizhik et al. 2001; Brizhik 2008). Since all these mechanisms are intimately related to each cell’s functions, BPE analysis was proposed as a noninvasive descriptor at deep quantum level of biological systems (Cohen and Popp 1997; Chang 2008; Popp et al. 1994; Hossu and Rupert 2006) and it was suggested to be a global indicator of viability, reactivity, and health of a living organism (Popp et al. 1994; Bajpai 2003; Hossu and Rupert 2006).

Since cancer is one of the major causes of death any new in vivo and in vitro study could potentially reflect into life-saving protocols. Understanding molecular events including luminescence in cancer could provide helpful insights on the action mechanism of various therapies, whereas monitoring cells behavior through luminescence could also help in identifying specific points of intervention into cellular functions. Few attempts were performed to measure the intrinsic BPE of cancer cells (Grasso et al. 1992; Amano et al. 1995; Kim et al. 2005a, b, 2006) indentifying mostly the differences between cancer and normal tissues. Based on these results BPE was also proposed as a possible noninvasive imaging method to identify cancer (Kim et al. 2006; Takeda et al. 2004; Popp 2009).

On the other hand silver nanoparticles (AgNP) were extensively evaluated for their interaction with biological systems, mostly for their antimicrobial and antiseptic properties (Lansdown 2006; Chen and Schluesener 2008; Rai et al. 2009). AgNP’s low toxicity for normal cells and their intrinsic antimicrobial characteristics might be of benefit if they will also be used in cancer therapy (Nowack 2010). However, recent data show that in higher concentrations, AgNP may be cytotoxic (El Badawy et al. 2011; Hackenberg et al. 2011; AshaRani et al. 2009), effect that may be detrimental for normal physiology but helpful in oncology. It was also shown that in a plant system AgNP intensify BPE (Hossu et al. 2010) without interfering with normal plant curing mechanisms; however, no data are available for correlation between intrinsic BPE of cancer cells and AgNP. Therefore this BPE study of cancer cells in the presence of AgNP will provide a window into direct effect of these NPs onto high energetic cellular processes, without the interferences from external intervention. Since one major therapeutic mechanism in cancer is based on reactive oxygen species (ROS) mainly singlet oxygen (1O2) and 1O2 is also involved in BPE we specifically tested the correlation between BPE and 1O2 generation in the presence of AgNP.

Materials and methods

Chemicals used were of analytical grade from Sigma Chemical Co. (St. Louis, MO) and used without further purification. 1O2 chemiluminescent sensor: trans-1-(2′-Methoxyvinyl)pyrene (MVP) was purchased from Invitrogen (Carlsbad, CA) and diluted to a concentration of 10 μM before use. Sodium azide (NaN3) solution was prepared in 10 μM concentration. AgNP were prepared according to previously described methods by standard wet chemical synthesis based on reduction reactions (Huang et al. 2007; Zhang et al. 2008; Hossu et al. 2010). The initial dimensions of AgNPs were estimated to be 6–20 nm, verified by dynamic light scattering and transmission electron microscopy as shown in Fig. 1. They were kept in a separate dark storage chamber at room temperature. The initial concentration was estimated at 10−8 M (6 × 109 NP/μL) based on chemistry ratios and confirmed using absorption spectrometry.

HR TEM of AgNP in low and high magnification (insert). Relative spherical shape of the particles is seen in low magnification and fringes of crystalline structure are seen in high magnification

A photon counting system (Hamamatsu Photonics K.K., Hamamatsu, Japan) was used to observe time-dependent photon emission intensity. The system is equipped with a H6180-1 photomultiplier tube (PMT) providing a maximum spectral response from 240 to 630 nm and a C8855 counting system, operating at room temperature. The gate time for collecting the photon signal from the PMT was set at 1 s. The measuring room was light proofed with dark materials and only a red radiological safe light was used during the manipulation of the chemicals and cells to minimize delayed luminescence. The PMT was placed inside a custom made dark chamber equipped with thermostat controlled heating pad and the dark count was measured at the beginning of each experiment to ensure that its value was at the level of the instrument noise, i.e., seven to nine counts per second (CPS). This insured that any signal recorded was from the sample and not due to transient changes of a residual light in the room or in the dark chamber. The distance between the PMT and the sample was 5 mm in all measurements. Each set of data consisting of up to 10,000 measurements was recorded using C8855’s operating software (Hamamatsu, Japan) and processed using Microsoft®️ Office Excel™️ 2007 and OriginPro™️ 8.5.0.

Note this is a sales site so I can't speak to efficacy, according to the site on "About" section the device is FDA approved. I guess somebody needs to create an "Anti-photon" device to really get things balanced properly Idea .... Cr6:  (Light for stimulating Biophotons)

The BioPhoton 100 Professional

More Stimulating Light

The BioPhoton 100 Professional has mixed-spectrum Blue Light and 850 and 940nm far infrared light. It has been shown that blue light stimulates lymph activity, promotes healing of cutaneous injuries (burns, cuts, and contusions) and even helps to combat MRSA. The benefits of 850nm and 940nm near Infrared light include increased ATP production, vasodilation in injured tissues of arteries, lymphatics, and veins, stimulation of stem cells, reduced inflammation, relief of pain, myofascial release, increased delivery of oxygen into the mitochondria, increased production of collagen, and boosts immunity.

How Does Photon Therapy Work?

Photon therapy emits packets of light called photons. Photons break the painful inflammatory cycle by dilating small blood and lymphatic vessels. This increase in circulation removes the irritating inflammatory products and results in accelerated healing and pain relief. The immune system and nervous system are also stimulated by photons, which increases activity and leads to faster repair of damaged tissues.

Numerous tests show that the increase in circulation and reduction in pain associated with the use of photons is the result of an increase in the release of nitric oxide directly under the neurotransmitter.

60 years ago, Furchgott (et al JPETT 113:22, 1955) demonstrated the ability of photo energy to induce vasorelaxation. Furchgott, Ignatto, and Murad were awarded the Nobel Prize in Medicine in 1998 for their work in identifying nitric oxide as the molecule responsible for regulating blood pressure.

The Science Behind It

Photon, or near-infrared light therapy works at the cellular level in a phenomenon known as Photobiomodulation. Photons stimulate cytochrome-c oxidase, an enzyme associated with the third part of the electron transport chain inside the mitochondria. Cytochrome-c oxidase in turn causes increased levels of ATP synthase, an enzyme associated with the fourth part of the electron transport chain. ATP synthase synthesizes ATP production which has a cascade of beneficial effects at the cellular level.

Here Are the Effects of the BioPhoton 100 After Just a Few Treatments

Infrared imaging, or thermography, is used to detect changes in blood circulation. A baseline infrared image may be taken before therapy and used to determine the proper course of treatment. This image is then stored on the computer system. After an initial course of 4-6 treatments, the scan is repeated. Changes in blood circulation are noted and used to assess the efficacy of treatment and determine prognosis.

Below are some examples of pre- and post-treatment infrared scans. Orange to red warmer colors in the pretreatment images indicate inflammation and pain. Patients experiencing numbness and poor circulation before treatment show warmer colors after treatment indicating increased blood circulation.

Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) Painful-neuropathy-pre-2
Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) Painful-neuropathy-post-2


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Post by Cr6 on Mon Mar 19, 2018 12:16 am

Increased Level of Extracellular ATP at Tumor Sites: In Vivo Imaging with Plasma Membrane Luciferase

Patrizia Pellegatti ,
Lizzia Raffaghello ,
Giovanna Bianchi,
Federica Piccardi,
Vito Pistoia,
Francesco Di Virgilio

PLOS Published: July 9, 2008



There is growing awareness that tumour cells build up a “self-advantageous” microenvironment that reduces effectiveness of anti-tumour immune response. While many different immunosuppressive mechanisms are likely to come into play, recent evidence suggests that extracellular adenosine acting at A2A receptors may have a major role in down-modulating the immune response as cancerous tissues contain elevated levels of adenosine and adenosine break-down products. While there is no doubt that all cells possess plasma membrane adenosine transporters that mediate adenosine uptake and may also allow its release, it is now clear that most of extracellularly-generated adenosine originates from the catabolism of extracellular ATP.
Methodology/Principal Findings

Measurement of extracellular ATP is generally performed in cell supernatants by HPLC or soluble luciferin-luciferase assay, thus it generally turns out to be laborious and inaccurate. We have engineered a chimeric plasma membrane-targeted luciferase that allows in vivo real-time imaging of extracellular ATP. With this novel probe we have measured the ATP concentration within the tumour microenvironment of several experimentally-induced tumours.

Our results show that ATP in the tumour interstitium is in the hundrends micromolar range, while it is basically undetectable in healthy tissues. Here we show that a chimeric plasma membrane-targeted luciferase allows in vivo detection of high extracellular ATP concentration at tumour sites. On the contrary, tumour-free tissues show undetectable extracellular ATP levels. Extracellular ATP may be crucial for the tumour not only as a stimulus for growth but also as a source of an immunosuppressive agent such as adenosine. Our approach offers a new tool for the investigation of the biochemical composition of tumour milieu and for development of novel therapies based on the modulation of extracellular purine-based signalling.



There is growing awareness that the tumour microenvironment has a key role in supporting tumour growth and in dictating the rules of host-tumour interaction [12], [5]. The tumour may wield host response by inducing the formation of protected niches that allow survival of cancer stem cells and their differentiation into mature cancer cells [13]. The tumour microenvironment which includes infiltrating inflammatory cells as well as stromal cells, is responsible for creating conditions that hinder the effectiveness of the host immune response and lead to immunoevasion, or even to tumour progression [14]. The biochemical composition of the tumour microenvironment is poorly known, but it is understood that it may profoundly change depending on tumor type and the host immunocompetence [15].

Depending on the tight balance between tumour-induced or tumour-released immunosuppressive factors and host-derived immunoactivating factors the microenvironment creates favourable or unfavourable conditions for tumour growth. This generates a network of facilitating or inhibitory interactions the effect of which is extremely difficult to anticipate. In this context hypoxic conditions that characterize several tumours may be an important component of the mechanism of tumour protection. Hypoxia causes the activation of hypoxia-inducible factor 1 α (HIF-1α) and accumulation of extracellular adenosine. Both factors are in principle very important in supporting tumour growth as HIF-1α controls angiogenesis and adenosine exerts a profound immunosuppressive activity, thus protecting the tumour from inflammatory cells. Recent data show that solid tumours have a gradient of adenosine concentration from the centre to the periphery, higher than the surrounding healthy tissue [6]. In addition, many tumours over-express enzymes involved in the catabolism of extracellular nucleotides and in the generation of adenosine [16]. Furthemore, glioblastoma cells injected in vivo together with apyrase show a reduced ability to produce tumours [17]. Accumulation of adenosine into the tumour microenvironment does not only protect tumour cells from the immune response, but may also exert a trophic effect on the tumour itself by stimulating endothelial cell proliferation and angiogenesis [18], [19], [20].

Although cells express carriers that may mediate adenosine translocation into the extracellular milieu, most extracellular adenosine is generated at the expenses of extracellular ATP via extracellular nucleotidases (ecto-ATPases and 5′-nucleotidase) [21], [22]. However, ATP in the tumour microenvironment is important not only as a source of adenosine but also for its intrinsic activity. In fact ATP itself modulates inflammation by triggering IL-1 maturation and release, dendritic cell differentiation by inducing a Th2-skewing phenotype and cell proliferation or cell death, depending on the concentrations and the activation of individual P2 receptors [23]. In addition, its has been recently shown that ATP causes shedding of metalloproteases (MMP9) [24] and expression of indoleamine oxygenase [25]; both activities may be very relevant for tumour progression as MMP9 release facilitates tumour invasion while indoleamine oxygenase has immunosuppressive activity.

Bioluminescence imaging is increasingly recognized as a powerful tool to study in vivo transcriptional regulation, signal transduction, activation of cancer-specific genes. So far, luciferase has been almost exclusively used as an intracellular reporter, to monitor the activity of specific transcriptional activators such as for example the estrogen receptor [26] or NF-κB [27]. In this study we show that cells engineered with luciferase can be also used to probe the extracellular space and to analyze the biochemical composition of the tumour microenvironment. Furthermore, since an increased ATP concentration is a feature of inflammation, engineering inflammatory cells with pmeLUC will make possible in vivo imaging of inflammation. Finally, since appending proper target sequences to luciferase may allow targeting to specific regions of the plasma membrane, we anticipate that pmeLUC may even allow to probe changes in the extracellular ATP concentration at restricted sites of cell-to-cell interaction.


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Post by Cr6 on Mon Mar 19, 2018 12:43 am

Cell Metab. 2016 Dec 13;24(6):795-806. doi: 10.1016/j.cmet.2016.09.013. Epub 2016 Oct 27.
Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice.
Mills KF1, Yoshida S2, Stein LR1, Grozio A1, Kubota S3, Sasaki Y4, Redpath P5, Migaud ME5, Apte RS6, Uchida K2, Yoshino J7, Imai SI8.
Author information


NAD+ availability decreases with age and in certain disease conditions. Nicotinamide mononucleotide (NMN), a key NAD+ intermediate, has been shown to enhance NAD+ biosynthesis and ameliorate various pathologies in mouse disease models. In this study, we conducted a 12-month-long NMN administration to regular chow-fed wild-type C57BL/6N mice during their normal aging. Orally administered NMN was quickly utilized to synthesize NAD+ in tissues. Remarkably, NMN effectively mitigates age-associated physiological decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective anti-aging interventions in humans.


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Post by Cr6 on Sat Mar 24, 2018 12:43 am

Toxins (Basel). 2015 Nov 3;7(11):4507-18. doi: 10.3390/toxins7114507.
Cytotoxic indole alkaloids against human leukemia cell lines from the toxic plant Peganum harmala.
Wang C1, Zhang Z2, Wang Y3, He X4.
Author information


Bioactivity-guided fractionation was used to determine the cytotoxic alkaloids from the toxic plant Peganum harmala. Two novel indole alkaloids, together with ten known ones, were isolated and identified. The novel alkaloids were elucidated to be 2-(indol-3-yl)ethyl-α-L-rhamnopyranosyl-(1 → 6)-β-D-glucopyranoside (2) and 3-hydroxy-3-(N-acetyl-2-aminoethyl)-6-methoxyindol-2-one (3). The cytotoxicity against human leukemia cells was assayed for the alkaloids and some of them showed potent activity. Harmalacidine (compound 8, HMC) exhibited the highest cytotoxicity against U-937 cells with IC50 value of 3.1 ± 0.2 μmol/L. The cytotoxic mechanism of HMC was targeting the mitochondrial and protein tyrosine kinase signaling pathways (PTKs-Ras/Raf/ERK). The results strongly demonstrated that the alkaloids from Peganum harmala could be a promising candidate for the therapy of leukemia.

Abstract Title:

Cytotoxicity of alkaloids isolated from Peganum harmala seeds.
Abstract Source:

Pak J Pharm Sci. 2013 Jul ;26(4):699-706. PMID: 23811445

Abstract Author(s):

Fatima Lamchouri, Mustapha Zemzami, Akino Jossang, Abdellatif Abdellatif, Zafar H Israili, Badiaa Lyoussi
Article Affiliation:

Fatima Lamchouri

Peganum harmala is used in traditional medicine to treat a number of diseases including cancer. Our preliminary studies show that the alkaloidal extract of PH seed is cytotoxic to several tumor cell lines in vitro and has antitumor effect in a tumor model in vivo. The present investigation was aimed at extending our previous studies in identifying the components in P. harmala seed-extract responsible for the cytotoxic effects, and study the cytotoxic and antiproliferative activity of isolated alkaloids and total alkaloidal fraction (TAF) in several tumor cell lines. Four alkaloids: harmalicidine, harmine, peganine (vasicine) and vasicinone were isolated from the P. harmala seed-extract and their activity and that of TAF were tested a) for their cytotoxic activity against four tumor cell lines [three developed by us by chemical-induction in Wistar rats: 1) Med-mek carcinoma ; 2) UCP-med carcinoma ; 3) UCP-med sarcoma] ; and 4) SP2/O-Ag14, and b) for antiproliferative effect on cells of Jurkat, E6-1 clone (inhibition of incorporation of {(3)H-thymidine} in cellular DNA). The alkaloids and TAF inhibited the growth of tumor cell lines to varying degrees; Sp2/O-Ag14 was the most sensitive, with IC50 values (concentration of the active substance that inhibited the growth of the tumor cells by 50%) ranging between 2.43μg/mL and 19.20 μg/mL, while UCP-med carcinoma was the least sensitive (range of IC50 = 13.83 μg/mL to 59.97 μg/mL). Of the substances evaluated, harmine was the most active compound (IC50 for the 4 tumor cell lines varying between 2.43 μg/mL and 18.39 μg/mL), followed by TAF (range of IC50 =7.32 μg/mL to 13.83 μg/mL); peganine was the least active (IC50 = 50 μg/mL to>100μg/mL). In terms of antiproliferative effect, vasicinone and TAF were more potent than other substances: the concentration of vasicinone, and TAF needed to inhibit the incorporation of {(3)H-TDR} in the DNA cells of Jurkat, E6-1 clone by 50% (IC50) were 8.60 ± 0.023 μg/mL and 8.94 ± 0.017 μg/mL, respectively, while peganine was the least active (IC50>100μg/mL). The IC50 values for harmalacidine (27.10 ± 0.011 μg/mL) and harmine (46.57 ± 0.011 μg/mL) were intermediate. The harmala alkaloids inhibited the growth of four tumor cell lines, and proliferation of Jurkat cells with varying potencies. Harmine was the most potent in inhibiting cell growth, and vasicinone was most active as antiproliferating substance. The TAF had significant cytotoxic as well as antiproliferating activity.
Article Published Date : Jun 30, 2013
Study Type : In Vitro Study
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Substances : Syrian rue : CK(1) : AC(1)
Diseases : Cancers: All : CK(14773) : AC(4596)
Pharmacological Actions : Antiproliferative : CK(2546) : AC(1685)

Effects of Syrian Rue as a MAOI inhibitor - Cox-2 source (anti-cancer) -- must listen show:

Episode 2 – William J. Walsh
Optimizing Your Brain via Biochemistry

Our performance and quality of life is largely dependent on a delicate balance of brain biochemistry. It defines our mental health, mood, our anxiety, our focus and attention, cognitive performance and ultimately even our personality.

Today’s guest estimates that 80 to 90% of the population have some kind of biochemistry abnormality that affects their brain. This is based on insights from a database of biochemistry he has collected over 35 years with over 3 million biochemistry test assays. So while many of us may not be included within the 26% of the population included in clinical diagnoses for mental disorders, most of us can improve our mental wellbeing or cognitive performance by addressing biochemistry imbalances.

Today’s guest is Dr. William J. Walsh, founder of the Over his 35 year career he has treated 30,000 patients with a wide range of brain related disorders, successfully treating them by addressing biochemical, methylation and epigenetic abnormalities. The treatments are nutrient based to realign biochemistry, and thus drug free.

William is also a frequent lecturer at conferences across the world including organizations such as the American Psychiatric Association, the U.S. Senate and the National Institutes of Mental Health. In short, he’s got a very in long and deep CV backed up by those 35 years of experience.
“In the areas of depression and behavior disorders and ADD and even schizophrenia… about 95%… have those conditions because of their abnormal biochemistry and by correcting and normalizing these brain chemicals, we were able to help most of them.”
– William J. Walsh PhD

This is a great interview that goes into a lot of depth in biochemistry, the labs, as well as looking at the emerging area of epigenetics and how work there will help us resolve more health issues and optimizing your brain via biochemistry.

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Post by Cr6 on Sat Mar 24, 2018 1:30 am

Syrian Rue has carved its name into the chronicles of time. Michelangelo used Syrian Rue (known also by its Latin name – Peganum harmala). Leonardo da Vinci said Syrian Rue is “miracle smart nutrient”. In the Middle East it is known as Esfand where its use dates back to pre-Zoroastrian ancient times . Most references to Syrian Rue in Persian history involve the use of magick. Greeks refer to it as Persaia botane. Shakespeare referred to it in his writings, although his personal use of it is unknown. Traces have been found in the hair of Egyptian mummified bodies.

When whole seeds are placed on hot charcoals the seeds explode like popcorn, releasing a fragrant smoke. It it very likely that the ancient “Soma Plant” is Syrian Rue by another name for the somatic science that surrounds it. Pedanius Dioscorides documented that Syrian Rue not only antidotes snake poisons but all deadly poisons, including poison mushrooms, scorpions, spiders, and mistletoe. Syrian Rue is also recommended for fevers with rigors(chills). Serapio calls it ‘the ultimate medicine against the evil of poisons’. Syrian Rue was used by thieves who robbed the houses of plague victims under the protection of their aromatic repellent. It is also known as the “anti-plague” plant. After the assignation of his father by poison, Mithridates King of Pontus studied poisons and used Syrian Rue to protect himself.

In addition to all the ancient documentation about Syrian Rue, more recent scientific observations from research teams around the world (fully referenced below) prove that the fluorescent harmala beta-carboline alkaloid combined with all the other alkaloids in Syrian Rue is arguably magical or contains a synergy of alkaloids which is responsible for the unusual combination of it being antibacterial, antiviral, and antiparasitic, as well as antimutagenic and antigenotoxic.

In 2007 it was first proposed that Syrian Rue might help with diabetes, by 2015 independent studies are reporting success with Rue, in 2017 now we know Type 2 diabetics might be able to achieve a reversal of their condition and Type 1 diabetes patients are able to produce healthy new pancreatic beta cells. Researchers all around the world are finding , documenting, and sharing the details of their discovery surrounding the healing powers of Syrian Rue, therefore we are not forced to blindly trust ancient knowledge as we consider the following modern science:

Growth Inhibitory Impact of Peganum harmala L. on Two Breast Cancer Cell Lines

The P. harmala extract exposure against two cancer cell lines, MDA-MB-231 and Mcf-7. In conclusion, the results of the current research address the anti-cancer effect of P. harmala L. to its alkaloid components mainly hamine and harmaline. It is suggested to perform further studies to elucidate the mechanism of action of both harmine and harmaline on more human cancer cell lines and eventual use of these herbal active principle compounds in future anti-cancer pharmaceutical is considerable.

Article 2, Volume 12, Issue 1, Winter 2014, Page 8-14 XML PDF (655 K)
Document Type: Research Paper
DOI: 10.5812/ijb.18562
Sahar Seyed Hassan Tehrani; Somayeh Hashemi Sheikh Shabani; Sattar Tahmasebi Enferadi ; Zohreh Rabiei

Vaginitis still remains as a health issue in women. It is notable that Candida albicans producing biofilm is considered a microorganism responsible for vaginitis is hard to treat. Peganum harmala was applied as an anti fungal in treatment for many infections in Iran. Therefore, this study goal to investigate the role of P. harmala in inhibition of biofilm formation in C. albicans. Results demonstrated that P. harmala in concentration of 12 μg/ml easily inhibited strong biofilm formation.

Osong Public Health and Research Perspectives Volume 7, Issue 2, April 2016, P 116-118
Elham Aboualigalehdari, Nourkhoda Sadeghifard, Morovat Taherikalani, Zaynab Zargoush, Zahra Tahmasebi, Behzad Badakhsh, Arman Rostamzad, Sobhan Ghafourian, Iraj Pakzad

The cytotoxic effects of peganum harmala were evaluated on six malignant cancer cells. Total alkaloids of the different parts were cytotoxic towards practically all cancer cell lines with IC50 ranging 1–52 µg/mL after 72 h of treatment. These data indicate that P. harmala alkaloids extract may support the traditional claims regarding its anticancer uses which could be helpful in providing of new cytotoxic agents against chemo-resistant cancer cells.

European Journal of Integrative Medicine Volume 9, January 2017, Pages 91-96
Lamine Bournine, Sihem Bensalem, Sofiane Fatmi, Fatiha Bedjou, Véronique Mathieue, Mokrane Iguer-Ouada, Robert Kisse, Pierre Duez

Peganum harmala has been shown to have antibacterial and anti-protozoal activity (cures protozoan infections also), including antibacterial activity against drug-resistant bacteria.

J. Nat. Prod. 44 (6): 745. PMID 7334386. doi:10.1021/np50018a025
Al-Shamma A, Drake S, Flynn DL

P harmala seeds extract showed significant in vitro and in vivo antileishmanial activities. Cutaneous leishmaniasis (CL), an endemic disease in many tropical and subtropical areas, including central and southern parts of Iran, continues to present serious treatment problems. The disease, although usually self-limiting, can cause considerable morbidity and may result in severe disfigurement. P. harmala, vasicine (peganine), has been found to kill the protozoan parasite Leishmania donovani.

Journal of Research in Medical Sciences. 2011 Aug; 16(Cool: 1032–1039.
Parvaneh Rahimi-Moghaddam, Soltan Ahmed Ebrahimi, Hourmazd Ourmazdi, Monawar Selseleh, Maryam Karjalian, Giti Haj-Hassani, Mohammad Hossein Alimohammadian, Massoud Mahmoudian, and Massoumeh Shafiei

P. harmala has appreciable efficacy in destroying intracellular parasites in the vesicular forms. Because of its appreciable efficacy in destroying intracellular parasites as well as non-hepatotoxic and non-nephrotoxic nature, harmine, in the vesicular forms, may be considered for clinical application in humans.

Journal of Drug Targeting,
2004 Apr;12(3):165-75.
Lala S, Pramanick S, Mukhopadhyay S, Bandyopadhyay S, Basu M

In this study, we investigated the protective effects of Peganum harmala seeds extract (CPH) against chronic ethanol treatment. Hepatotoxicity was induced in male Wistar rats by administrating ethanol 35% (4?g/kg/day) for 6 weeks. CPH was co-administered with ethanol, by intraperitonial (IP) injection, at a dose of 10?mg/kg bw/day. Control rats were injected by saline solution (NaCl 9‰). Chronic ethanol administration intensified lipid peroxidation monitored by an increase of TBARS level in liver. Ethanol treatment caused also a drastic alteration in antioxidant defence system; hepatic superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities. A co-administration of CPH during ethanol treatment inhibited lipid peroxidation and improved antioxidants activities. However, treatment with P. harmala extract protects efficiently the hepatic function of alcoholic rats by the considerable decrease of aminotransferase contents in serum of ethanol-treated rats.

Archives of Physiology and Biochemistry – The Journal of Metabolic Diseases
Volume 121, Issue 2 Published online: 14 May 2015
Ezzeddine Bourogaa, Raoudha Mezghani Jarraya, Mohamed Damak & Abdelfattah Elfeki

Mice? It was 1999 then – from mice to men that is evolution in the end.

Peganum harmala seed extracts also show effectiveness against various tumor cell lines, both in vitro and in vivo. Results obtained indicate that alkaloids of Peganum have a high cell toxicity in vitro. The active principle at a dose of 50 mg/kg given orally to mice for 40 days was found to have significant antitumoural activity. Peganum harmala alkaloids thus possess significant antitumour potential, which could prove useful as a novel anticancer therapy.

1999 Nov-Dec;54(6):753-8.
Lamchouri F, Settaf A, Cherrah Y

Plant derived agents may exert a new approach to the treatment of leukaemia. The present study was an evaluation of proliferation, cytotoxicity and differentiation of harmine and harmaline on HL60 cells, alone or in combination with ATRA and G-CSF. Counting of cells, viability, MTT assay, morphology, NBT reduction and flow cytometry analysis were performed using CD11b and CD 14 monoclonal antibodies. The data showed that harmine and harmaline reduced proliferation in dose and time dependent manner. This shows that the direction of differentiation is dominantly determined by ATRA. These preliminary data implies a new approach in treatment of leukemia.

Archives of Pharmacal Research July 2007, Volume 30, Issue 7, pp 844
Farhad Zaker, Arezo Oody, Alireza Arjmand

Twelve indole alkaloids, including two novels, were purified and identified from P. harmala. The chemical structures were determined by spectroscopic and chemical methods. The cytotoxicities against five human leukemia cell lines were assayed for the alkaloids. Some alkaloids showed potent cytotoxicity against human leukemia cells. Harmalacidine (HMC) showed the highest cytotoxicity against U-937, which could induce cell apoptosis. The results suggest that the alkaloids have perfect selectivity for human leukemia cells.

Toxins (Basel). 2017 May; 9(5): 150.
Published online 2017 Apr 28. doi: 10.3390/toxins9050150
Yuan Li, Yunli Zhao, Xia Zhou, Wei Ni, Zhi Dai,Dong Yang, Junjun Hao, Lin Luo, Yaping Liu,Xiaodong Luo, and Xudong Zhao

The beta-carboline alkaloids present in medicinal plants, such as Peganum harmala and Eurycoma longifolia, have recently drawn attention due to their antitumor activities. Further mechanistic studies indicate that beta-carboline derivatives inhibit DNA topoisomerases and interfere with DNA synthesis. Moreover, some beta-carboline compounds are specific inhibitors of cyclin dependent kinases (CDKs). In this study we used budding yeast as a model system to investigate the antitumor mechanism of beta-carboline drugs. We found that DH334, a beta-carboline derivative, inhibits the growth of budding yeast.

Cancer and Biological Therapy, 2007 Aug;6(Cool:1193-9. Epub 2007 May 4.Li Y, Liang F, Jiang W, Yu F, Cao R, Ma Q, Dai X, Jiang J, Wang Y, Si S.

We report the in vivo antioxidative properties of the aromatic (harmane, harmine, harmol) and dihydro-beta-carbolines (harmaline and harmalol) studied by using Saccharomyces cerevisiae strains proficient and deficient in antioxidant defenses. Their antimutagenic activity was also assayed in S. cerevisiae and the antigenotoxicity was tested by the comet assay in V79 cell line, when both eukaryotic systems were exposed to H(2)O(2). We show that the alkaloids have a significant protective effect against H(2)O(2) and paraquat oxidative agents in yeast cells, and that their ability to scavenge hydroxyl radicals contributes to their antimutagenic and antigenotoxic effects.

Mutagenesis. 2007 Jul;22(4):293-302. Epub 2007 Jun 1.
Moura DJ, Richter MF, Boeira JM, Pêgas Henriques JA, Saffi J

Gamma-harmine exhibited relatively good radioprotective effect. Gamma-harmine is the first alkaloid isolated from a plant having protective effects against whole-body lethal irradiation in mice

Yao Xue Xue Bao. 1995;30(9):715-7..

A 2016 study investigated the antimicrobial activity of Harmal ( Peganum harmala) aqueous extracts against two fungi (Aspergillusniger and Peniciliumitalicum) and two Gram negative bacteria (Escerichia coli and Salmonellatyphi). The Harmal methanolic extracts were found to inhibit mycelial radial growth of both fungi. This effect was found to be significant at first day of the experiment as well as the last days. Mycelial fresh and dry weights of both fungi were also greatly reduced with harmal extracts. The higher concentration of Harmal gave the maximum effect which decreased with dilution. The effect on mycelial growth was more pronounced on P.italicum than on A.niger. The effect of Harmal leaves extract on the two bacteria (E.coli and S.typhi) was evaluated by the inhibition zone and dilution methods. A clear zone of inhibition was shown by the extracts against both bacteria, although the inhibition was less against E.coli. The results of the dilution plate method showed that the log number of colonies of both bacteria was highly decreased with Harmal extract; however, S.typhi was more susceptible and greatly affected by the extract.

Journal of Microbiology Research, p-ISSN: 2166-5885 e-ISSN: 2166-5931, 2016
Abdel Moneim E. Sulieman, Ahmed A. Alghamdi, Vajid N. Veettil, Nasir A. Ibrahim

According to test results, P. harmala seeds extract showed potent antioxidant activity with IC50 values ranging between 40-129 µg/ml. In case of antibacterial assay, P. harmala seeds showed better inhibitory activity than leaves against both strains i.e. Staphylococcus aureus and Pseudomonas aeruginosa with values ranging between 70 to 100% while in case of antifungal assay water-acetone extract of seeds showed significant antifungal effect against Aspergillus niger. In terms of cytotoxic assay, hexane extract of seeds of were more cytotoxic against shrimp larvae (LD50 = 57.07 µg/ml). Aqueous extract of leaves of and acetone extract of seeds showed < 80% mortality in antileishmanial assay. GC-MS analysis revealed that leaves and seeds contain some important biological metabolites. It is concluded that selected plants could be a potential source of antileishmanial, antibacterial, antifungal and anticancer lead compound. Hence it is indicated to further investigate this plant in vitro as well as in vivo for new drug discovery.

International Journal of Biosciences, 9(1), 45-58, July 2016.
Zainab Gul Kanwal, Abdul Hafeez, Ihsan Ul Haq, Tofeeq-Ur-Rehman, Syed Aun Muhammad, Irum Shazadi, Nighat Fatima, Nisar Ur Rehman

Introduction: Benign prostatic hyperplasia (BPH) is considered as a major cause of lower urinary tract symptoms (LUTS) in older men and its most common sign is nocturia. Objectives: This study aimed to determine the effect of the seeds of Peganum harmala compared with tamsulosin on alleviating urinary symptoms in patients with BPH. Patients and Methods: In this single blind clinical trial study, 90 patients diagnosed with BPH and LUTS, based on international prostate standard survey (IPSS) were divided into three groups. The first group was received oral capsule of P. harmala, the second group was administered tamsulosin with oral P. harmala seed and the third group was received tamsulosin drug and they were evaluated after 4 weeks. Results: The results showed that the difference between mean scores of IPSS was significant after the intervention (P=0.001). Besides, the mean of IPSS in the three groups was significantly different (P=0.001) (the first group 41.9±5.3, the second group 21.0±4.4 ,the third group 16.5±3.7 respectively). However, after the intervention, patients in the second group had the lowest average on most indicators of IPSS but the difference was only significant about urinary frequency, nocturia and intermittency(P<0.05). Conclusion: Application of Peganum harmala seed can be useful in reducing urinary symptoms in patients with BPH.

Journal of Renal Injury Prevention 2017 ;6(2):127-131. PMID: 28497089
Majid Shirani-Boroujeni, Saeed Heidari-Soureshjani, Zahra Keivani Hafshejani

Syrian Rue exhibits antisecretory and cytoprotective properties and is successfully treating gastric ulcers.
Phytomedicine Volume 20, Issue 13, 15 October 2013, Pages 1180-1185
Biochem Biophys Res Commun. 2011 Jun 3; 409(2):260-5

Two different studies showed bone anabolic effects of harmine. These findings suggest that harmine, as the main alkaloid of P. harmala, may be useful for treatment of some bone diseases. Harmine promotes osteoblast differentiation through bone morphogenetic protein signaling.

Yonezawa T, Lee JW, Hibino A, Asai M, Hojo H, Cha BY, Teruya T, Nagai K, Chung UI, Yagasaki K, Woo JT
European Journal of Pharmacology 2011 Jan 15; 650(2-3):511-8.

Using X-ray crystallographic analysis, Ten new alkaloids (peganumine B-I and two enantiomers), containing five β-carbolines, three quinazolones were isolated from the ethanol extract of Peganum harmala seeds testing their measured potential cytotoxicity and cholinesterase inhibitory activities.

DOI: 10.1039/C6RA00086J (Paper) RSC Adv., 2016, 6, 15976-15987
Ya-di Yang, Xue-mei Cheng, Wei Liu, Zhu-zhen Han, Gui-xin Chou, Ying Wang, Du-xin Sun, Zheng-tao Wang and Chang-hong Wang

Rats? Diabetic humans has been done already….

In 2016, a study indicated that hydroalcoholic extract of Peganum harmala seeds possesses antidiabetic and hypolipidemic activities in streptozotocin-induced diabetic male rats.

Cholesterol, Volume 2016 (2016), Article ID 7389864, 6 pages
Gholamreza Komeili, Mohammad Hashemi, and Mohsen Bameri-Niafar

Rats again… I have never heard of a human Parkinson’s Disease study with Syrian Rue, I expect to see one in 2018 if not by the close of 2017…..

Another 2016 study finds Peganum Harmala L. Extract Reduces Oxidative Stress and Improves Symptoms in 6-Hydroxydopamine-Induced Parkinson’s Disease in Rats.

Iran J Pharm Res. 2016 Winter;15(1):275-81. PMID:27610168 PMCID:PMC4986102
Rezaei M, Nasri S, Roughani M, Niknami Z, Ziai SA.

A 2016 study found that Syrian Rue fights dental plaque. An ethanolic extract of P. harmala can inhibit the growth of S. mutans. Despite the higher inhibitory effect of 0.2% chlorhexidine compared to 50 mg/mL of this extract, other studies indicate that higher concentrations of P. harmala extract can have similar or greater inhibitory effect against microorganisms. However, high cell toxicity of this extract on cells limits the use of this plant as an antimicrobial agent (like mouthwash) in oral cavity. Even if limited to low concentrations, either lonely or in combined preparations, its application might be more useful for resistant bacteria compared to the routine available mouthwashes. Further antimicrobial and cytotoxicity studies on animals or human subjects are needed to obtain more accurate and applicable results.

Journal of dentistry (Shiraz), 2016 Sep; 17(3): 213–218. PMCID: PMC5006831
Mohammad Motamedifar, Hengameh Khosropanah, and Shima Dabiri

The extract of Peganum harmala was used topically to treat certain dermatoses of inflammatory nature. Results were encouraging and proved the antibacterial, antifungal, antipruritic and probably antiprotozoal effects of the extract.

International Journal of Dermatology, May 1980, DOI:10.1111/j.1365-4362.1980.tb00305.x
El-Saad El-Rifaie M

In very very extremely large doses, Syrian Rue is an abortifacient in humans.

In a study on cattle, the curative effect of P. harmala was better than that of diminazene aceturate and produced minimal side effects proven safe for pregnant animals. It was concluded that the total alkaloid of P. harmale showed a marked effect as a treatment for haemosporidican infections in cattle.

Trop Anim Health Prod. 1997 Nov;29(4 Suppl):72S-76S.
Hu T, Fan B, Liang J, Zhao S, Dang P, Gao F, Dong M


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Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) Empty Re: Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor)

Post by Cr6 on Sat Mar 24, 2018 1:51 am

More on P. harmala and anti-tumor effects...

Pharmacogn Rev. 2013 Jul-Dec; 7(14): 199–212.
doi:  10.4103/0973-7847.120524
PMCID: PMC3841998
Pharmacological and therapeutic effects of Peganum harmala and its main alkaloids
Milad Moloudizargari, Peyman Mikaili,1 Shahin Aghajanshakeri, Mohammad Hossein Asghari, and Jalal Shayegh2
Author information ► Article notes ► Copyright and License information ►
This article has been cited by other articles in PMC.

Wild Syrian rue (Peganum harmala L. family Zygophyllaceae) is well-known in Iran and various parts of this plant including, its seeds, bark, and root have been used as folk medicine. Recent years of research has demonstrated different pharmacological and therapeutic effects of P. harmala and its active alkaloids, especially harmine and harmaline. Analytical studies on the chemical composition of the plant show that the most important constituents of this plant are beta-carboline alkaloids such as harmalol, harmaline, and harmine. Harmine is the most studied among these naturally occurring alkaloids. In addition to P. harmala (Syrian rue), these beta-carbolines are present in many other plants such as Banisteria caapi and are used for the treatment of different diseases. This article reviews the traditional uses and pharmacological effects of total extract and individual active alkaloids of P. harmala (Syrian rue).
Keywords: Harmine, harmaline, peganum harmala, pharmacological effects, wild syrian rue


Harmal[1] (Peganum harmala L. family Zygophyllaceae) is a perennial, glabrous plant which grows spontaneously in semi-arid conditions, steppe areas and sandy soils, native to eastern Mediterranean region. It is a shrub, 0.3-0.8 m tall with short creeping roots, white flowers and round seed capsules carrying more than 50 seeds. The plant is well-known in Iran and is widely distributed and used as a medicinal plant in Central Asia, North Africa and Middle East.[2,3,4,5] It has also been introduced in America and Australia. Dried capsules – mixed with other ingredients – are burnt as a charm against “the evil eye” among Iranians.[2] This plant is known as “Espand” in Iran, “Harmel” in North Africa and “African rue,” “Mexican rue” or “Turkish rue” in the United States.[6] Various parts of P. harmala including its seeds, fruits, root, and bark, have been used as folk medicine for a long time in Iran and other countries [Table 1]. Many pharmacological surveys have shown different effects of P. harmala [Table 4] and/or its active alkaloids (particularly harmaline) [Table 5].
Table 1
Table 1
Traditional uses of Peganum harmala
Table 4
Table 4
Chemical compounds of P. harmala
Table 5
Table 5
Toxic doses of various alkaloids of Peganum harmala

Studies carried out on the chemical composition of the extracts show that beta-carboline and quinazoline alkaloids are important compounds of this plant [Figure 1]. In one study, the concentration of harmaline in different parts of the plant including seeds, fruits, and capsule walls was determined by Reverse phase high-performance liquid chromatography (RP-HPLC) as 56.0 mg/g, 4.55 mg/g and 0.54 mg/g, respectively.[7] Although, harmaline and harmine are the most important alkaloids that are generally responsible for their beneficial effects, numerous studies show that other alkaloids present in P. harmala also have some roles in the pharmacological effects of the plant.[8] Harmaline (C13H15ON2) was first isolated by Göbel from the seeds and roots of P. harmala and is the major alkaloid of this plant.[6] In addition to P. harmala (Harmal), beta-carboline alkaloids are present in many other plants such as Banisteriopsis caapi (Malpighiaceae). They are also constituents of Ayahuasca, a hallucinogenic beverage ingested in rituals by the Amazonian tribes.[7] This article completely reviews the pharmacological effects of P. harmala [Table 2] and its active ingredients [Table 3].[6,7]
Table 2
Table 2
Pharmacological effects of Peganum harmala
Table 3
Table 3
Pharmacological effects of alkaloids of Peganum harmala
Figure 1
Figure 1
Molecular structure of major alkaloids of peganum harmala


P. harmala is one of the most frequently used medicinal plants to treat hypertension and cardiac disease worldwide.[9,85] It has also been shown in various pharmacological studies that P. harmala extract or its main active alkaloids, harmine, harmaline, Harman and harmalol, have different cardiovascular effects such as bradycardia, decreasing systemic arterial blood pressure and total peripheral vascular resistance, increasing pulse pressure, peak aortic flow and cardiac contractile force,[10] Vasorelaxant[11,12] and angiogenic inhibitory effects.[13]
Vasorelaxant and antihypertensive effects

The aqueous (AqE) extract of the seeds of P. harmala have antispasmodic, anticholinergic, antihistaminic and antiadrenergic effects.[14] One study on the cardiovascular effects of harmine, harmaline and harmalol indicated that these three alkaloids have vasorelaxant effects with rank order of relaxation potency of harmine >harmaline >harmalol. In case of the first two alkaloids this vasorelaxant activity was not only attributed to their interaction with the alpha 1-adrenergic receptors in vascular smooth muscles but also more importantly to their increasing effect on notric oxide (NO) release from the endothelial cells, which was dependent on the presence of external Ca2+. Harmalol had no effect on the release of NO from the endothelial cells and it weakly interacted with the cardiac 1,4-dihydropyridine binding site of L-type Ca2+ channels (Ki value of 408 microM).[11] In the same study, the vasorelaxant activity of harman, another active alkaloid of P. harmala, was shown with a mechanism of interaction with the L-type Ca2+ channels and increasing NO release from the endothelial cells so dependent on the presence of external Ca2+. These effects of harman may be involved in its hypotensive activity.[15] Another study indicates that the action of harmaline on the prostacyclin pathway also plays a role in its vasoleraxant activity.[12] It has been also shown that harmaline, harmalol and harmine decrease systemic arterial blood pressure and total peripheral vascular resistance obviously not due to activation of cholinergic, beta-adrenergic and histamine (H1) receptors. The harmaline-evoked decreases were frequently followed by a secondary increase and these two effects of harmalol were inconsistent.[10] Astulla et al. also showed in an in vitro study the vasorelaxant activity of vasicinone, another alkaloid isolated from the seeds of P. harmala, against phenylephrine-induced contraction of isolated rat aorta.[16]

Effects on the heart

There have been a few studies conducted regarding the direct effects of P. harmala extract and its alkaloids on heart muscle. For example, in one study it was shown that three P. harmala isolated alkaloids (Harmine, Harmaline and Harmalol) have ionotropic effect and also decrease heart rate in normal anesthetized dogs. Since neither vagotomy nor atropinization affected the harmala-induced bradycardia it became evident that the decrease in heart rate was not due to a negative chronotropic effect of the alkaloids.[10]

In another in vivo study, harman dose-dependently produced transient hypotension and long-lasting bradycardia in anesthetized rats.[11] Harmaline inhibits both 45Ca2+ uptake and efflux in cardiac sarcolemal vesicles in a dose-dependent manner.[17]

Angiogenic inhibitory effect

It was revealed in a study that harmine is a potent angiogenic inhibitor. This substance can significantly decrease the proliferation of vascular endothelial cells and reduce expression of different pro-angiogenic factors such as vascular endothelial growth factor, NO and pro-inflammatory cytokines. Nuclear factor-κB and other transcription factors like cAMP response element-binding (CREB) and Activating transcription factor 2 (ATF-2) involved in angiogenesis were also inhibited by harmine. Moreover, harmine decreased production of other factors by tumor cells, which play a significant role in angiogenesis like cyclooxygenase (COX-2), inducible nitric oxide synthase, and matrix metalloproteases.[13]
Inhibitory effect on platelet aggregation

The alkaloids of P. harmala are also shown to have anti-platelet aggregation effects.[18] However, there is not so much evidence on this effect of the plant so far.


In traditional medicine, P. harmala has been used among societies to treat some nervous system disorders such as Parkinson's disease,[19] in psychiatric conditions[7] such as nervosity,[20] and to relieve rigorous pain.[21] The alkaloid content of P. harmala is shown to be psychoactive[22] and various in vitro and in vivo studies indicate a wide range of effects produced by P. harmala and its active alkaloids on both central and peripheral nervous system including, analgesia,[22,23] hallucination, excitation,[24] and anti-depressant effect.[25,26]

Some of these alkaloids such as harmaline, harmine, and norharmane are also endogenous compounds present in the body and since they have been found in high plasma concentrations in alcoholics,[27] drug addicts,[28] smokers,[29] and patients with Parkinson's disease,[30] they are thought to be crucially involved in various central nervous system (CNS) problems.

It has been also proven that P. harmala-derived beta-carbolines interact with opioid,[21] dopamine,[24] GABA (Gamma-Aminobutyric acid),[31] 5-hydroxytryptamine, benzodiazepine, and imidazoline[32] receptors present in the nervous system and this way induce their many pharmacological effects. Moreover, these alkaloids are neuroprotective[31,33] and strong inhibitors of monoamine oxidase and this important feature makes them a preferable target in the treatment of some conditions like depression.[25]

Mono amine oxidase inhibition and anti-depressant effect

Beta-carbolines present in P. harmala strongly inhibit monoamine oxidase enzyme that is the main factor in degradation and reuptake of monoamines like serotonin and norepinephrine. It was pointed out in an in vitro study that seed and root extracts of P. harmala significantly inhibits MAO-A but has no effect on MAO-B. In case of the seed extract the inhibitory effect was reversible and competitive with an IC50 of 27 μg/l and it was mostly attributed to harmaline and harmine. The strong inhibitory effect of the root extract was only due to harmine and the IC50 was calculated as159 μg/l.[7] It could be concluded that this inhibitory effect has the potential to reverse the MAO-mediated monoamine reduction in depression. Harmine at high doses increased the BDNF (Brain-derived neurotrophic factor) protein level, which is decreased in depressive conditions, while imipramine, a common anti-depression drug, had no such effect.[25] Farzin et al. revealed in a study on the anti-depressant effects of harmane, norharmane, and harmine using the mouse force swim test that these alkaloids of P. harmala have a significant dose-dependent anti-depressive effect with a suggested mechanism of acting on benzodiazepine receptors. It was shown in another in vitro study that the extract of P. harmala has the ability to inhibit catechol-O-methyltransferase and thereby the methylation of catecholamines with a mixed type mechanism.[34] All of these effects represent an idea that P. harmala and its derivatives could be used for treatment of mood disorders and are potent alternatives for current anti-depression drugs.

Analgesic and antinociceptive effects

The analgesic effect of different forms of P. harmala extract (ethyl acetate [EAE], butanolic [BE], and AqE) have been investigated in various parallel studies. The methods used in these studies include formalin, hot plate, and writhing tests. The results showed that all forms of the extracts produced the analgesic effect. Among the extracts, BE showed the maximum effect with a percentage of 35.12% in the writhing test. In case of the AqE, the nociceptive effect was only observed in the second phase of the formalin test. Treatment with both EAE and BE produced a dose-dependent analgesia. Since treatment with naloxone prevented the nociceptive effect of the extracts, it is concluded that an opioid-modulated mechanism is involved. The results also indicated that the extracts act both centrally and peripherally.[21,23,35]

Relation with Parkinson's disease

The endogenous harmala alkaloids have been proven to be involved in Parkinson's disease.[31] One study on both endogenous and exogenous beta-carbolines showed that they all have general DAT-mediated (Dopamine active transporter-mediated) dopaminergic toxicity and therefore, are involved in the pathogenesis of Parkinson's disease.[36] Adversely, it was revealed in an in vitro study that two of these endogenous compounds, norharman and 9-methylnorharman, have good anti-parkinsonism effects via inhibition of MAO-B, an enzyme involved in the production of parkinsonism-related substances from the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. However, naturally occurring beta-carbolines had almost no such inhibitory effect.[33]

In contrast, several studies on the anti-parkinsonism effect of B. caapi revealed that its beta-carboline content (harmine and harmaline) has significant effect against this disease through the inhibition of MAO-B.[37,38] Although, these beta-carbolines with anti-parkinsonism effect are also present in P. harmala, there have been no studies conducted regarding the possible effect of P. harmala isolated alkaloids against Parkinson's disease, thus far.

Other neuropsychological effects

There have been reports of other effects produced by P. harmala in the nervous system.

In an in vitro study desoxypeganine, one of the P. harmala alkaloids, dose-dependently decreased ethanol consumption in female Alko alcohol rats with no effect on food and fluid consumption.[39] This may represent a safe way to decrease the consumption of alcohol in alcoholics. Harmane, another alkaloid isolated from P. harmala induced amnesia with a suggested mechanism of interaction with dopaminic (D1 and D2) receptors.[24] Harmaline and harmane have been shown to modulate voltage-activated calcium- ICa (V)-channels in vitro and in a reversible and use independent manner.[31]


Various studies have shown different antiparasidal,[16,40] antifungal,[41,42] antibacterial[41,43] and insecticidal[44,45] effects of the alkaloids derived from P. harmala seeds. It has also been used widely as an anti-fungal[42] and antiparasidal[46] agent in traditional medicine of some parts of the world. For instance, in Saudi Arabia it has been so common to use P. harmala against fungal infections.[42] In one study, the methanolic, AqE and chloroform extracts of P. harmala were shown to have respectively strong, moderate, and slight inhibitory effects on the growth of Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger and Candida albicans.[42]

Preparations of P. harmala were also used in folk medicine of South-Eastern Spain as anti-leishmanial remedies.[46] Moreover, its powdered seeds and various extracts have been used as a remedy against tapeworm infections in men and animals in the indigenous system of medicine.[40]

Antiprotozoal effect

Various studies have been carried out investigating in vitro and in vivo effects of different P. harmala extracts on forms of leishmania parasites. One study on the effect of P. harmala extract on Leishmania infantum revealed that harmine and harmaline have weak anti-leishmanial activity against both promastigote and amastigote form of the parasite. At the same time, harmaline showed strong toxicity against the amastigote forms inside the macrophages. The suggested mechanism for this property is the inhibitory effect of harmaline on protein kinase C (PKC) action of the parasites.[47] Another study compared the in vitro antileishmanial activity of antimonyl tartrate and P. harmala extract against L. major. During this study the extract showed the same potency as antimonyl tartrate that means it could be a good alternative for the antimonial drugs as the first-line antileishmanial treatments with lots of severe side effects.[48] The effectiveness of the extract is mostly attributed to its beta-carboline content. P. harmala extract also decreased the lesion size and number of the parasites in cutaneous form of the disease.[49] In addition to the beta-carbolines, peganine another alkaloid of P. harmala, was shown to have strong in vitro and in vivo toxicity against both amastigotes and promastigotes of Leishmania donovani. A dose of 100 mg/kg body weight of peganine was effective against visceral leishmaniasis in hamsters.[50]

There have been several studies indicating effectiveness of P. harmala extract against theileriosis.[51,52] Two studies were conducted in Iran on the effect of P. harmala extract with a dose of 5mg/kg body weight once daily for 5 days on cattle[52] and sheep[51] theileriosis that showed a significant recovery rate of respectively 78% and 65%.

Beta-carbolines from the seeds of P. harmala showed strong trypanosomicidal activity against nifurtimux-resistant LQ strain of Trypanosoma cruzi. Inhibition of respiratory chain appears to be the possible determinant of this action of beta-carbolines.[53]

Furthermore, there have been reports of antiplasmodial activity of different P. harmala alkaloids such as vasicinone, deoxyvasicinone, and beta-carbolines.

Antibacterial activity

One of other important features of P. harmala alkaloids is their bactericidal activity that is comparable with that of common antibiotics, which have many adverse effects. Different species of bacteria have been shown to be susceptible to these alkaloids. For example Proteus vulgaris and Bacillus subtilis appeared to be very sensitive to harmine.[41] The activity of these alkaloids depended on the microorganism and the application method. For instance, the methanolic extract showed higher antibacterial potency against all tested micro-organisms (Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and P. vulgaris) than other chloroform and petroleum extracts in one study.[43]

It is concluded that P. harmala and its alkaloids could probably be used for the control of antibiotic resistant isolates of bacteria.[54]

Insecticidal and antifungal activity

In vitro treatment with individual alkaloids of P. harmala or a mixture of them was so efficient against A. niger and C. albicans with a minimal inhibitory concentration of total (crude) alkaloids respectively 0.333 ± 0.007 MIC (Minimum inhibitory concentration) (mg/ml) and 0.333 ± 0.007 MIC (mg/ml).[41] A synergistic activity of different alkaloids present in the crude extract might be involved in its strong effect.

Furthermore, there have been some reports about insecticidal activity of P. harmala-derived beta-carbolines indicating their inhibitory effects on the development and growth of the larval stages of some insects. For example harmaline prevented the development of larvae of Plodia interpunctella, an insect pest of stored food, to the pupal and adult stages.[44] This inhibitory effect of harmaline was due to its severe toxicity on the epithelial cells of the midgut that finally leads to shedding of the cytoplasm contents into the midgut lumen.

Another study showed the insecticidal activity of methanolic P. harmala extract against Tribolium castaneum, the stored grain pest. Larvae growth was significantly inhibited with the incorporation of the extract into their diet. The adult form of the insect was also susceptible. It could be a good idea to use P. harmala as a tool to control the population of such harmful insects.[45]

Antineoplasm, antiproliferative and antioxidant effects

Since ancient times, P. harmala has been used by traditional healers to make various preparations in the treatment of cancers and tumors in some parts of the world.[13,55] For example, it has been so common in traditional medicine of Morocco to use powdered seeds of P. harmala to treat skin and subcutaneous tumors.[56] The seed extract of P. harmala is the main component of a very common ethnobotanical preparation used against different cancers and neoplasms in Iran, namely Spinal-Z.[57,58]

The antitumor activity of P. harmala and its active alkaloids (mainly beta-carbolines) have also drawn attentions of many researchers worldwide that has led to various pharmacological studies regarding this important effect of P. harmala.[23,56] Various authors have reported cytotoxicity of P. harmala on tumor cell lines in vitro and in vivo. In one study, the methanolic extract of P. harmala reduced significantly proliferation of three tested tumor cell lines (UCP-Med (a tumor cell line), Med-mek carcinoma, and UCP-Med sarcoma) in all concentrations. This anti-proliferative effect was produced by the alkaloid fraction of the extract in the first 24 h of the treatment. A cell lysis effect was observed in the next 24 h and thus, resulted in complete cell death within 48 to 72 h.[56] The same results were observed with the total extract of the plant in another study. The extract also showed cytotoxicity against artificially grafted subcutaneous Sp2/O cell-line in BALB-c (Albino) mice.[56] Administration of different beta-carboline alkaloids isolated from P. harmala showed inhibitory effect against Lewis Lung cancer sarcoma-180 or HepA tumor in mice at rates of 15.3-49.5%. Substitution of formate at R3 and aryl at R9 of the tricyclic skeleton respectively decreased neurotoxicity and increased the inhibitory effects of the alkaloids that made them ideal agents to be used as novel antitumor drugs with lesser side effects.[55] Several in vitro and in vivo studies have revealed that these cytotoxicity and antitumor effects of P. harmala are related to its interaction with RNA,[59] DNA and its synthesis,[56,60] and inhibition of human Topoisomerase.[58] In a study conducted in Iran, it was shown using the DNA relaxation assay that the extract of P. harmala inhibits human DNA Topoisomerase I. This effect was attributed to the beta-carboline content of the extract and potency of the alkaloids were determined as harmine >harmane >harmaline in a way that treatment with the total extract showed weaker inhibitory effect than treatment with every individual alkaloid.[58] Another study indicated that harmine and its derivatives have inhibitory effect on human Topoisomerase I activity but no effect on Topoisomerase II. Intercalation of several carbolines into eukaryotic DNA has also been reported by many authors.[58,61] This intraction of beta-carbolines cause significant structural changes in DNA and interfere with its synthesis.[56,61] The alkaloid-DNA binding affinity was ordered as harmine >harmalol >harmaline >harmane >tryptoline. There are also other suggested mechanisms for the anti-tumor activity of P. harmala alkaloids. In an in vitro study by Li et al., budding yeast was used as a model to investigate the anti-tumor activity of P. harmala. Results showed that DH334, a beta-carboline derivative and an anticancer drug, specifically inhibits cyclin dependent kinases (CDKs) and blocks the initiation of cell cycle at the G1 phase. It also inhibited the kinase activity of Cdk2/CyclinA (a member of the cyclin family) in vitro. This could be another possible mechanism for the antitumor activity of the drug.[56,93]

Many pharmacological studies suggest an antioxidant and free radical scavenging effect of P. harmala. This effect has been attributed to the increasing effect of P. harmala extract on E2 (17β-estradiol) level as an important antioxidant and reactive oxygen species (ROS) scavenger.[12,62,63] In another study, the effects of harmaline and harmalol were tested on Digoxin-induced cytochrome P450 1A1 (CYP1A1), a carcinogen-activating enzyme, in human hepatoma HepG2 cells. These alkaloids significantly inhibited the enzyme via both transcriptional and posttranslational mechanisms in a concentration-dependent manner.[3] Ethanol and chloroform extracts of P. harmala showed protective effects against thiourea-induced carcinogenicity by normalization of neuron-specific enolase and thyroglobulin levels in animal models.[64] Other effects of the plant extract such as anti-proliferative effect on Leukemic cell lines,[65] inhibitory action on the metastasis of melanoma cells, inducing apoptosis in melanoma cells,[66] tumor angiogenesis inhibition,[13] and binding to RNA[61] have also been reported by various authors. In some cases, P. harmala showed a higher selectivity towards malignant cells than common anticancer drugs like doxorubicin.[57] All of these data suggest that P. harmala and its alkaloids possess the potential to be used as novel antioxidant and anti-tumor agents in anti-cancer therapy.


P. harmala has been used traditionally as an effective emmenagogue and abortificient agent in the Middle East, India, and North Africa.[6,56,67] It has also been shown that abortion happens frequently among animals that digest this plant in a dry year.[8,68] Quinazoline alkaloids (e.g., vasicine and vasicinone) within P. harmala have been attributed to the abortificient effect of this plant.[8]


P. harmala extract and powdered seeds have been used in folk medicine of different parts of the world to treat colic in man and animals.[40] The efficiency of this plant in treatment of colic is due to its antispasmodic effect[69] probably as a result of blocking different types of intestinal calcium channels[70] by the alkaloid content of the plant specially harmaline. P. harmala also possesses noticeable nauseant[71] and emetic[7,72] effects.


Two different studies conducted by Yonezawa et al. showed bone anabolic effects of harmine, in vivo and in vitro.[73,74] It was revealed that administration of 10 mg/kg/day of harmine inhibits formation and differentiation of osteoclasts in mice via down-regulation of c-Fos (A cellular proto-oncogene) and NFATc1 (Nuclear factor of activated T-cells, cytoplasmic 1) and thus, prevents osteoclast-mediated resorption. Adversly, it enhances osteoblast differentiation probably via inducing the expression of BMPs and activation of bone morphogenetic protein (BMP) and Runx2 pathways. It was also found that carbon C3C4 double-bond and 7-methoxy group of harmine plays an important role in these processes. These findings suggest that harmine, as the main alkaloid of P. harmala, may be useful for treatment of some bone diseases.


Beta-carboline alkaloids of P. harmala are shown to have immune-modulatory effects in several studies.[26,75] Extracts of this plant have significant anti-inflammatory effect via the inhibition of some inflammatory mediators including prostaglandin E2 (PGE2) (100 μg/mg) and tumor necrosis factor alpha (TNF-α) (10 μg/mg).[46]


P. harmala has been traditionally used to treat diabetes in folk medicine of some parts of the world.[69,76] This effect of P. harmala has been pharmacologically confirmed in several studies one of which showed that the plant would lose its hypoglycemic activity at high doses instead of increasing it.[77] Harmine is the main alkaloid of P. harmala that is involved in its anti-diabetic effect.[25] One study shows that harmine regulates the expression of peroxisome proliferator-activated receptor gamma (PPARγ), the main regulator of adipogenesis and the molecular target of the thiazolidinedione antidiabetic drugs, through inhibition of the Wnt signaling pathway. Therefore, it mimics the effects of PPARg ligands on adipocyte gene expression and insulin sensitivity without showing the side-effects of thiazolidinedione drugs such as weight gain.[78]


In addition to all therapeutic effects of P. harmala, there have been several reports of human[79] and animal[68] intoxications induced by this plant. There are also experimental studies indicating P. harmala toxicity.[6,7] In an in vitro study, intrapretoneal administration of three different extracts of P. harmala at a dose of 50 mg/kg body weight induced sympthoms such as: Abdominal writhing, body tremors and slight decrease in locomotor activity,[21] while oral administration of these extracts showed no toxicity. There have been also the same symptoms reported in different human cases[2,6,80] following ingestions of P. haramala seed extract or infusion including: Neuro-sensorial symptoms, visual hallucination, slight elevation of body temperature, cardio-vascular disorder such as bradycardia and low blood pressure, psychomotor agitation, diffuse tremors, ataxia and vomiting. Despite animal intoxications in almost all of human cases, P. harmala poisonings were relieved in a few hours.[6] P. harmala extract is toxic at high-doses[7,77,81,82] and can cause paralysis, liver degeneration, spongiform changes in the central nervous system,[83] euphoria, convulsions, digestive problems (nausea, vomiting), hypothermia and bradycardia.[2,6,68,80] However, therapeutic doses have been reported to be safe in a rodent model.[54]

MAO inhibition activity of P. harmala components are the main cause for the toxicological effects after ingestion of the plant.[7] Moreover, the intercalation of P. harmala alkaloids into DNA has led to its mutagenic property which causes genotoxic effects.[84] P. harmala methanolic extract has showed teratogenic effects in female rats.[68] The extract prolonged diestrus phase, reduced number of living pups, and decreased the number of resorption. It also dose-dependantly decreased litter size.[8] These data all together suggest that care should be taken while using P. harmala and its derivatives as therapeutic agents in order to prevent probable intoxications.


P. harmala is shown to interact with drug metabolism due to its significant effects on the expression of cytochrome P450s (CYP), the most important superfamily of drug metabolizing enzymes. Seeds of this plant dose-dependently increase the expression of CYP1A2, 2C19, and 3A4 whereas decrease the expression of CYP2B6, 2D6 and 2E1. Harmine and harmaline are the main contents involved. These data all together suggest that care should be taken when P. harmala is co-administered with other drugs.[3]


Our aim in preparing this paper was to show the traditional usage and previously confirmed pharmacological effects of P. harmala as one of the most well-known medicinal plants in Iran and to illustrate it's potential to be used as a novel source for the development of new drugs based on the most recent associated studies. As it is evident from this study, P. harmala has a wide range of pharmacological effects including cardiovascular, nervous system, gastrointestinal, antimicrobial, antidiabetic, osteogenic, immunomodulatory, emmenagogue, and antitumor activity among many other effects. Beta-carboline alkaloids contained in P. harmala are the most important contents of the plant responsible for most of its pharmacological effects. Since there have been many reports of intoxications following ingestion of specific amounts of P. harmala seeds, care should be taken by scientists and clinicians regarding usage of this plant for therapeutic purposes until adequate studies confirm the safety and quality of the plant. Finally, based on this information, this review provides the evidence for other researchers to introduce P. harmala as a safe and effective therapeutic source in the future.

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Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) Empty Re: Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor)

Post by Cr6 on Sat Mar 24, 2018 2:08 am

Advantages of Glycolysis For Cancer

While some people see glycolysis in cancer cells as a byproduct of damaged mitochondria, it is also possible that cancer cells have adapted to favor glycolysis for its growth promoting properties.Not only does glycolysis produce energy more rapidly that aerobic respiration, but it actually promotes an environment where cancer cells can rapidly divide.

Excess lactic acid produced by cancer cells actually shuts off the body’s anticancer immune response by deactivating anti-tumor immune cells (2). This essentially shields cancer from the immune system.

At the same time, rapid cell growth requires a lot of raw materials to make new cells. One of the primary atoms needed in abundance to form new cell structures is carbon. Carbon atoms are linked together to form backbones that cell structures are built off of.

After glucose is metabolized, it leaves a 6-carbon chain. While aerobic respiration excretes this carbon through the breath via carbon dioxide, glycolysis retains it. It is thought that this allows for a more rapid division of cells through a higher availability of raw materials.

10 Ways Cancer Impacts Cancer
How Sugar Feeds Cancer Growth

As has been covered so far, cancer cells have an impaired ability to produce energy. Due to damaged mitochondrial structures, they perform glycolysis rather than aerobic respiration. As a result, they must upregulate glucose intake in order to support rapid division and growth.

At the same time glycolysis favors cancer growth in several ways. This why a ketogenic diet has been heavily investigated for being able to limit cancer growth by cutting off its primary fuel supply. In addition to this, there are other mechanisms by which sugar feeds cancer growth.

Sugar Inhibits Immune System Function
White Blood Cells

White blood cells are the soldiers of our immune system. They are a powerful force against foreign invaders in our bodies including cancer cells. In order to operate at their full capacity, they require high amounts of Vitamin C. This was discovered by Nobel Prize winner, Linus Pauling, in the 1960’s.

Unlike other animals, humans are not able to produce Vitamin C endogenously. Instead we must receive it from our foods and transport it to our cells for use. We then have internal antioxidant systems that help us to retain and recycle Vitamin C to get the most use out of it. This is a function of glutathione (3).

In the 1970’s Dr. John Ely discovered what is referred to as the Glucose-Ascorbate-Antagonism (GAA) Theory. Both glucose and Vitamin C are similar in structure and rely upon insulin in order to enter the cells via the Glut-1 receptor on the cell membrane. Unfortunately, glucose has a higher affinity for this receptor which means it is absorbed more readily than vitamin C.

It is thought that having high levels of blood sugar actually inhibits Vitamin C from entering the white blood cells, which drastically reduces immunity and therefore the ability to fight off cancer. So, while sugar feeds cancer, it also inhibits the immune system for acting upon cancer cells.

Linus Pauling Deficiency
Phagocytic Index

In order for white blood cells to destroy foreign pathogens within the body, they do so by engulfing them and essentially breaking them down into benign byproducts. This process is called phagocytosis. The measure of how well a white blood cell is able to perform this function is called the phagocytic index.

Therefore, in order to provide the best chance for the immune system to target cancer cells, they need to have a high phagocytic index.

Because of the relationship explained above between glucose and vitamin C, high levels of sugar circulating in the blood is thought to lower the phagocytic index of white blood cells, impairing their ability to fight cancer.  In fact, it has been shown that a blood sugar level of 120 actually reduces phagocytic index by 75% (4).

Sugar Vitamin C
Sugar Feeds Cancer via Insulin HMP Shunt

In addition to Vitamin C’s importance for proper phagocytic functioning of white blood cells, it is also critical for stimulation of the hexose monophosphate (HMP) pathway (5).

The HMP pathway produces NADPH which is used by white blood cells to make superoxide and reactive oxygen species that are used to destroy pathogens.  This HMP shunt also produces ribose and deoxyribose which provide important raw materials for the formation of new white blood cell RNA/DNA (6).

When the immune system is under attack it needs to quickly produce new immune cells.  If blood sugar is high enough to turn off the HMP shunt it will reduce the quantity of RNA/DNA and the amount of new immune cells formed.

Sugar Feeds Cancer via AMP-K

AMP-K stands for Adenosine Monophosphate-activated protein kinase. When ATP (Adenosine Triphosphate) is broken down for energy within cells, phosphate groups are removed to form ADP and AMP (Adenosine Diphosphate and Adenosine Monophosphate, respectively).

When the ratio of AMP to ATP is increased, it is a sign that energy is getting low and AMP-K signals the upregulation of ATP production. In this manner, AMP-K is an energy regulating molecule.

It has also been shown that upregulation of AMP-K diverts glucose away from cancer cells and towards the body’s healthy tissues (7). In fact, it is suggested that activation of AMP-K helps to reverse the glycolytic preference of cancer cells, giving them an energetic disadvantage (Cool.

Luckily, AMP-K activity can be upregulated by intense exercise, carbohydrate restriction, and intermittent fasting (9, 10).

There are a number of peripheral benefits of AMP-K activation that are centered around key physiological pathways that are also associated with cancer growth. These include mTOR, the p53 gene, and COX-2 enzymes.

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Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) Empty Re: Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor)

Post by Cr6 on Sat Mar 24, 2018 2:09 am

COX-2 Inhibition Potentiates Antiangiogenic Cancer Therapy and Prevents Metastasis in Preclinical Models

Lihong Xu1, Janine Stevens1, Mary Beth Hilton1,2, Steven Seaman1, Thomas P. Conrads3,*, Timothy D. Veenstra3, Daniel Logsdon2, Holly Morris4, Deborah A. Swing4, Nimit L. Patel5, Joseph Kalen5, Diana C. Haines6, Enrique Zudaire1 and Brad St. Croix1,†

See all authors and affiliations
Science Translational Medicine 25 Jun 2014:
Vol. 6, Issue 242, pp. 242ra84
DOI: 10.1126/scitranslmed.3008455


Antiangiogenic agents that block vascular endothelial growth factor (VEGF) signaling are important components of current cancer treatment modalities but are limited by alternative ill-defined angiogenesis mechanisms that allow persistent tumor vascularization in the face of continued VEGF pathway blockade. We identified prostaglandin E2 (PGE2) as a soluble tumor-derived angiogenic factor associated with VEGF-independent angiogenesis. PGE2 production in preclinical breast and colon cancer models was tightly controlled by cyclooxygenase-2 (COX-2) expression, and COX-2 inhibition augmented VEGF pathway blockade to suppress angiogenesis and tumor growth, prevent metastasis, and increase overall survival. These results demonstrate the importance of the COX-2/PGE2 pathway in mediating resistance to VEGF pathway blockade and could aid in the rapid development of more efficacious anticancer therapies.


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Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) Empty Re: Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor)

Post by Cr6 on Sat Mar 24, 2018 2:13 am

ATP Mediates NADPH Oxidase/ROS Generation and COX-2/PGE2 Expression in A549 Cells: Role of P2 Receptor-Dependent STAT3 Activation

Shin-Ei Cheng,
I-Ta Lee,
Chih-Chung Lin,
Wan-Ling Wu,
Li-Der Hsiao,
Chuen-Mao Yang


Published: January 11, 2013



Up-regulation of cyclooxygenase (COX)-2 and its metabolite prostaglandin E2 (PGE2) are frequently implicated in lung inflammation. Extracellular nucleotides, such as ATP have been shown to act via activation of P2 purinoceptors, leading to COX-2 expression in various inflammatory diseases, such as lung inflammation. However, the mechanisms underlying ATP-induced COX-2 expression and PGE2 release remain unclear.

Principal Findings

Here, we showed that ATPγS induced COX-2 expression in A549 cells revealed by western blot and real-time PCR. Pretreatment with the inhibitors of P2 receptor (PPADS and suramin), PKC (Gö6983, Gö6976, Ro318220, and Rottlerin), ROS (Edaravone), NADPH oxidase [diphenyleneiodonium chloride (DPI) and apocynin], Jak2 (AG490), and STAT3 [cucurbitacin E (CBE)] and transfection with siRNAs of PKCα, PKCι, PKCμ, p47phox, Jak2, STAT3, and cPLA2 markedly reduced ATPγS-induced COX-2 expression and PGE2 production. In addition, pretreatment with the inhibitors of P2 receptor attenuated PKCs translocation from the cytosol to the membrane in response to ATPγS. Moreover, ATPγS-induced ROS generation and p47phox translocation was also reduced by pretreatment with the inhibitors of P2 receptor, PKC, and NADPH oxidase. On the other hand, ATPγS stimulated Jak2 and STAT3 activation which were inhibited by pretreatment with PPADS, suramin, Gö6983, Gö6976, Ro318220, GF109203X, Rottlerin, Edaravone, DPI, and apocynin in A549 cells.


Taken together, these results showed that ATPγS induced COX-2 expression and PGE2 production via a P2 receptor/PKC/NADPH oxidase/ROS/Jak2/STAT3/cPLA2 signaling pathway in A549 cells. Increased understanding of signal transduction mechanisms underlying COX-2 gene regulation will create opportunities for the development of anti-inflammation therapeutic strategies.


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Post by Cr6 on Sat Mar 24, 2018 2:24 am

Taxifolin Suppresses UV-Induced Skin Carcinogenesis by Targeting EGFR and PI3K
Naomi Oi, Hanyong Chen, Myoung Ok Kim, Ronald A. Lubet, Ann M. Bode and Zigang Dong
DOI: 10.1158/1940-6207.CAPR-11-0397 Published September 2012

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Skin cancer is one of the most commonly diagnosed cancers in the United States. Taxifolin reportedly exerts multiple biologic effects, but the molecular mechanisms and direct target(s) of taxifolin in skin cancer chemoprevention are still unknown. In silico computer screening and kinase profiling results suggest that the EGF receptor (EGFR), phosphoinositide 3-kinase (PI3K), and Src are potential targets for taxifolin. Pull-down assay results showed that EGFR, PI3K, and Src directly interacted with taxifolin in vitro, whereas taxifolin bound to EGFR and PI3K, but not to Src in cells. ATP competition and in vitro kinase assay data revealed that taxifolin interacted with EGFR and PI3K at the ATP-binding pocket and inhibited their kinase activities. Western blot analysis showed that taxifolin suppressed UVB-induced phosphorylation of EGFR and Akt, and subsequently suppressed their signaling pathways in JB6 P+ mouse skin epidermal cells. Expression levels and promoter activity of COX-2 and prostaglandin E2 (PGE2) generation induced by UVB were also attenuated by taxifolin. The effect of taxifolin on UVB-induced signaling pathways and PGE2 generation was reduced in EGFR knockout murine embryonic fibroblasts (MEF) compared with EGFR wild-type MEFs. Taxifolin also inhibited EGF-induced cell transformation. Importantly, topical treatment of taxifolin to the dorsal skin significantly suppressed tumor incidence, volume, and multiplicity in a solar UV (SUV)-induced skin carcinogenesis mouse model. Further analysis showed that the taxifolin-treated group had a substantial reduction in SUV-induced phosphorylation of EGFR and Akt in mouse skin. These results suggest that taxifolin exerts chemopreventive activity against UV-induced skin carcinogenesis by targeting EGFR and PI3K. Cancer Prev Res; 5(9); 1103–14. ©️2012 AACR.


Skin cancer is one of the most common cancers in the United States. Each year, more than 1,000,000 new cases of skin cancers are reported in the United States, making up 40% of all diagnosed cancers (1). Chronic UV exposure is recognized as a major etiologic factor of skin carcinogenesis (2). The UV spectrum can be divided into 3 wavelengths, UVA (320–400 nm), UVB (280–320 nm), and UVC (200–280 nm; refs. 3, 4). Although UVC is filtered out by the ozone layer, UVA and UVB reach the surface of the earth. Of the UV irradiation that reaches the surface of the earth, 90% to 99% is composed of UVA and 1% to 10% is composed of UVB (4). UVA is carcinogenic and causes photoaging and wrinkling of the skin (5). UVB is mainly responsible for a variety of skin diseases including melanoma and nonmelanoma skin cancers because it is capable of triggering the initiation, promotion, and progression phases of skin cancer (6, 7). Therefore, targeting UV-induced signaling might be an effective strategy for preventing skin carcinogenesis.

The EGF receptor (EGFR) is activated by UV radiation (Cool. EGFR is a member of the receptor tyrosine kinase, and is reported to be activated and/or overexpressed in a variety of human cancers including UV-induced skin cancer (9, 10). UV irradiation rapidly activates EGFR through the induction of EGFR ligands and the inactivation of cytoplasmic protein tyrosine phosphatases that maintains low basal levels of phosphorylated EGFR (11–13). UV-activated EGFR in turn activates a number of signaling cascades, including extracellular signal–regulated kinases (ERK), p38 kinase, and c-jun-NH2-kinase (JNK), which are known regulators of cell division (14–16). In response to UV irradiation, EGFR also activates phosphoinositide 3-kinase (PI3K), leading to Akt activation and suppression of apoptosis (17). Therefore, the EGFR and PI3K/Akt signaling pathways are logical molecular targets for chemoprevention of UV-induced skin cancer.

Taxifolin, also known as dihydroquercetin, is a flavonone commonly found in onions (18), milk thistle (19), French maritime bark (20), and Douglas fir bark (21) in an aglycone or glycoside form. Taxifolin has multiple biologic effects, including antioxidant and anti-inflammatory effects, and plays a role in preventing cardiovascular disease (22–24). Recently, several studies have focused on taxifolin as a potential cancer chemopreventive agent. One study showed that aglycone form of taxifolin exerts chemopreventive effects through an antioxidant response element (ARE)-dependent mechanism in colon cancer cells (25). The taxifolin aglycone form is also reported to induce apoptosis in prostate cancer cells (26). Although these reports provide evidence that taxifolin might exert chemopreventive effects against several cancers, the molecular mechanisms and direct targets of taxifolin are still unclear. Herein, we report that taxifolin suppresses UVB-induced activation of signal transduction by directly inhibiting EGFR and PI3K in JB6 P+ mouse skin epidermal cells. Moreover, taxifolin strongly suppresses tumor incidence in a solar UV (SUV)-induced skin carcinogenesis mouse model. Thus, taxifolin acts as an inhibitor of EGFR and PI3K and is expected to have beneficial effects in the prevention of UV-induced skin carcinogenesis.


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Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) Empty Re: Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor)

Post by Cr6 on Sat Mar 24, 2018 2:35 am

2008 by the Association of Clinical Scientists, Inc.

Cancer Morphogenesis: Role of Mitochondrial Failure

Egil Fosslien

Department of Pathology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois

Address correspondence to Egil Fosslien, M.D., 502 Fairview Avenue, Glen Ellyn, IL 60137, USA; tel 630 469 6824; e-mail efosslie{at}


Adenosine triphosphate (ATP) required for normal cell metabolism is mainly supplied by mitochondrial oxidative phosphorylation (OXPHOS), which is limited by available oxygen and modulated by cell signaling pathways. Primary or secondary OXPHOS failure shifts cell metabolism towards ATP generation by glycolysis (Warburg effect). The objective of this paper is to clarify the role of mitochondrial dysfunction in cancer morphogenesis and to elucidate how faulty morphogen gradient signaling and inflammatory mediators that regulate OXPHOS can cause cancer-induced morphogenesis. Developmental morphogenesis and cancer morphogenesis are regulated by morphogenetic fields. The importance of morphogenetic fields is illustrated by transplantation of metastatic melanoma cells into the chick-embryo; the tumor cells adapt morphologies that resemble normal cells and function normally in the host. A morphogen gradient is a simple form of morphogenetic field. Morphogens such as those of the transforming growth factor (TGF)-β family inhibit and stimulate basic cell proliferation at high and low concentrations respectively. Along a signaling gradient of declining TGF-β concentration, with increasing distance from the gradient source, cell proliferation is first gradually less inhibited, and then gradually stimulated, thus generating a concave curved structure. In 3D cell cultures, TGF-β concentration determines the diameter of the tubules it induces. TGF-β1 can modulate mitochondrial OXPHOS via adenine nucleotide translocase (ANT) or uncoupling protein (UCP) via COX-2 and prostaglandin (PG) E2. Thus, gradients of TGF-β can regulate the radius of curvature of tissues by modulating mitochondrial ATP generation. Derailment of morphogen control of mitochondrial ATP synthesis can lead to abnormal spatial variation in ATP supply, abnormal spatial distribution of cell proliferation, and cancer morphogenesis. Involvement of COX-2 in morphogen signaling is a mechanism whereby inflammation can promote carcinogenesis. Restoration of OXPHOS can reverse cancer morphogenesis and restore normal tissue morphology. Avoiding exposure to environmental mitochondrial toxins and toxic food ingredients should reduce the risk of cancer.


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Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) Empty Re: Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor)

Post by Cr6 on Sat Mar 24, 2018 2:59 am

There is evidence that genetic markers (RNA codes) change even within different sections of a tumor.


Research provides better understanding of how some cancer cells resist treatment

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March 23, 2018

An international team of researchers led by Lucio Miele, MD, PhD, Professor and Chair of Genetics at LSU Health New Orleans School of Medicine, and Justin Stebbing, BM BCh MA, PhD, Professor of Cancer Medicine and Medical Oncology at Imperial College of Medicine in London, has found new genetic mutations that promote the survival of cancer cells. The research also provided a clearer understanding of how some cancer cells are able to resist treatment. The findings are published in PLOS ONE, available here.

"All cancers are caused by genetic damage, mutations to key genes that control the lives of cells," notes Dr. Miele, who also heads LSU Health New Orleans' Precision Medicine Program. "Mutant genes that cancers depend upon for survival are called 'driver' mutations."

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The researchers tested genes in 44 cancers that no longer responded to therapy. These are not often tested in clinical practice. The tumor types included breast, lung, colorectal, sarcomas, neuroendocrine, gastric and ovarian, among others. They found that these advanced cancers had selected many new possible "driver" mutations never described before, in addition to drivers already known -- the cancers had evolved new driver mutations to become resistant.

No two cancers were genetically identical, even cancers of the same organs that looked the same under a microscope. In some cases, the researchers found evidence that an individual cancer had evolved two or even three drivers in the same gene, a sign that multiple cancer cell clones had evolved in the same tumor that had found different ways of mutating a particularly important gene. Many of these new genetic mutations are in functional pathways that can be targeted with existing drugs.

"These findings imply that genomic testing should be performed as early as possible to optimize therapy, before cancers evolve new mutations, and that recurrent cancers should be tested again, because their driver mutation may be different from those that existed at diagnosis," says Miele.

With this information, therapy could be tailored to the evolving genomic picture of each individual cancer -- the hallmark of precision medicine.

"We are working toward a day when we won't have to give a patient the devastating news that a cancer has come back and isn't responding to chemotherapy," Miele concludes.


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Post by Cr6 on Wed Mar 28, 2018 12:46 am

Quantifying Cancer and Reexamining Which Cancers May be Inhibited by Fasts

Water fasting or ketogenic therapies may be effective with some cancers, and not with others. Learn about the PET scan and how it can provide insights into whether a cancer is likely to be responsive or not to the water fast tactic we’ve covered in previous episodes.

In this episode, we return to look at ketosis and water fasts as a tool to help treat cancer. This builds on the previous episodes looking at Ketosis with Jimmy Moore and the impact of water fasts on cancer with Dr. Thomas Seyfried.

In this episode, we dig deeper into the cancer topic looking at how ketogenic or low-carb diets may contribute via mechanisms related to insulin and ketones to inhibit cancer growth. We look at why only some types of cancers may benefit from these types of ketogenic treatments, and the data behind it. The data backing up this episode, is that of the PET scan — Positron Emission Tomography. PET Scans can be used to understand what type of cancer a person is dealing with and more importantly, whether it is likely to respond to ketogenic therapies or not.
“For cancers that are dependent on glutamine more than glucose… They can be aggressive… and they may not show up on a PET scan, and they also may not be responsive to a low carbohydrate diet.“
– Dr. Eugene Fine

Our guest is Dr. Eugene Fine. He’s currently a professor of Clinical Nuclear Medicine at the Albert Einstein College of Medicine. Most recently, in 2012, he published a study in the scientific journal of Nutrition on 10 cancer patients treated with a low-carb diet. He’s currently expanding his research by working on the use of low-carbohydrate diets combined with chemotherapy in animals.

This is all linked through his area of specialism, which is PET scans — positron emission tomography — where he has been identifying and monitoring cancers for the use of this type of scan. We’ll also touch on some of his studies looking at the impact of ketones, in vivo, on normal cells and malignant cells, and how that differs compared to glucose.

The episode highlights, biomarkers, and links to the apps, devices and labs and everything else mentioned are below. Enjoy the show and let me know what you think in the comments!

What You’ll Learn

   Reducing carbohydrates in diet and reducing insulin secretion in the body may inhibit cancer growth (4:06).
   How ketones inhibit cancer cells (10:06).
   Why are cancer cells over-expressing uncoupling protein 2 and reactive oxygen species (12:35)?
   Dr. Fine explains how he uses PET scans to identify many different types of cancerous cells and severity by using fluorodeoxyglucose, or FDG (17:32).
   If the cancer does not show up on the PET scan (as is the case with prostate cancer and glutamine dependent cancers) it may not respond to a low carbohydrate diet (23:57).
   Dr. Fine discusses quantitating the PET scans (30:50).
   Any inflamed area might also show up on the PET scan associated with the FDG (32:36).
   This research is in the beginning phase and needs to be studied on a larger scale as the next step (34:11).
   Dr. Fine describes his “recharge trial” where cancer patients were put on a low carbohydrate diet to observe the effects of the diet (35:00).
   During the trial the patient’s blood levels were measured to determine whether they were ketotic (37:42).
   Dr. Fine discusses the results of this recharge trial by identifying that inhibiting insulin may have effects on cancer progression/remission (40:31).
   Cancer may adapt to the environment where it “grew up”. So if you develop cancer already on an low carb diet, will not be affected by a low carb diet as an intervention (45:05).
   Damien and Dr. Fine discuss other ways to change ketone/insulin levels (49:44).
   High calorie versus low calorie diets are discussed (53:13).
   The biomarkers Gene Fine tracks on a routine basis to monitor and improve his health, longevity and performance (1:03:29).
   Gene Fine’s one biggest recommendation on using body data to improve your health, longevity and performance (1:09:14).

Eugene J. Fine, MD

   Dr. Fine: biography and publications.
   PubMed Results
   “Recharge” trial: Pilot study conducted by Dr. Fine. More information can be found here and on Dr. Fine’s website through Albert Einstein College of Medicine.

Tools & Tactics
Drugs & Supplements

   Metformin: A drug which is used to improve blood sugar regulation in diabetes. Researchers are looking at its wider applications with cancer treatment as it has been found to inhibit insulin secretion.
   Ketone esters and salts: A new range of supplements making ketone bodies directly available to the body and thus inducing ketosis. There are various forms including Beta Hydroxybutyrate Monoesters (BHB monoesters), and Beta Hydroxybutyrate mineral salts (BHB combined with Na+, K+, and Ca2+). One available for purchase is Ketosports KetoForce and Ketosports KetoCaNa.

Diet & Nutrition

   Low-carbohydrate diet: this programme limits carbohydrate consumption to increase ketosis. This was the main discussion point for this episode.
   Ketogenic diet: The ketogenic diet is a low carb diet which also raises the level of ketone bodies in the blood.


Episode 16 – Dr. Thomas Seyfried "Water Fasts" as a Potential Tactic to Beat Cancer

Show Notes

How the idea that a change in mitochondrial function is behind cancer started in the 1920s (4:10).
The ancient energy mechanism through which cancer cells can bypass the mitochondria through fermentation instead of normal mitochondrial respiration (7:20).
The part of mitochondrial function that seems to be compromised in cancer – oxidative phosphorylation (8:15).
Different types of cancer cells and tumors have varying damage to their mitochondria. The worst and most aggressive cancers have the least mitochondrial function (9:00).
The oncogenic paradox (9:00).
Lipids such as Cardiolipins in the inner membrane of mitochondria are the part responsible for respiration (15:10).
How Dr. Seyfried pooled research from over 50 years together to develop his conclusions on cancer and the mitochondria (18:00).
Therapeutic ketosis and fasting can enhance mitochondria (23:00).
Ketone bodies produce cleaner energy, with less oxidative stress (ROS) than glucose molecules, when used for fuel in the mitochondria (27:00).
Nuclear genetic mutations prevent cancer cells from adapting to use ketone bodies as their energy source (29:30).
Which biomarkers could be indicative of cancer risk? (33:10).
Using therapeutic fasting of several days to improve your metabolism (36:00).
Using combined blood glucose – ketone meters to take readings and using Dr. Seyfried’s calculator to calculate Glucose – Ketone Indices (38:00).
It requires 3 to 4 days of fasting to get into the therapeutic glucose – ketone index zone (42:00).
“Autolytic cannibalism” to improve overall mitochondrial function – the mitochondria can either be rescued, enhanced or consumed (47:30).
The difficulties with directly measuring mitochondrial respiration vs. anaerobic fermentation and lactic acid to assess cancer status (49:50).
Weight loss can come in two types, pathological and therapeutic. The weight loss via fasting is therapeutic and healthy (52:00).
Cancer patients do better with chemotherapy, with less symptoms, when they are in a fasted state (52:00).
Cancer centers currently do not offer mitochondrial based therapies, only chemo or immuno therapies (57:40).


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Post by Cr6 on Sat Mar 31, 2018 12:14 am

From an article posted earlier on Sirt1. UCP2 proteins are a conduit for normal energy creation in the mito-chondria:


Sirt1 and obesity-associated metabolic diseases

Hepatic metabolic derangements are key components in the development of fatty liver, insulin resistance, and atherosclerosis. Sirt1 is an important regulator of energy homeostasis in response to nutrient availability. Scientists demonstrated that hepatic Sirt1 regulates lipid homeostasis by positively regulating peroxisome proliferators-activated receptor α (PPARα), a nuclear receptor that mediates the adaptive response to fasting and starvation. Hepatocyte-specific deletion of Sirt1 impairs PPARα signaling and decreases fatty acid β-oxidation, whereas overexpression of Sirt1 induces the expression of PPARα targets. Sirt1 interacts with PPARα and is required to activate PPARα coactivator PGC-1α. When challenged with a high-fat diet, liver-specific Sirt1 knockout (KO) mice develop hepatic steatosis, hepatic inflammation, and endoplasmic reticulum stress [5]. Present research data indicate that Sirt1 plays a vital role in the regulation of hepatic lipid homeostasis and that pharmacological activation of Sirt1 may be important for the prevention of obesity associated metabolic diseases [5]. Other research also shows that manipulation of Sirt1 levels in the liver affects the expression of a number of genes involved in glucose and lipid metabolism [6]. Additionally, recent studies demonstrated that modest overexpression of Sirt1 resulted in a protective effect against high fat induced hepatic steatosis and glucose intolerance [7, 8]. Sirt1 orthologs also play a critical role in controlling SREBP-dependent gene regulation governing lipid/cholesterol homeostasis in metazoans in response to fasting cues. These findings may have important biomedical implications for the treatment of metabolic disorders associated with aberrant lipid/cholesterol homeostasis, including metabolic syndrome and atherosclerosis [9]. Sirt1 regulates uncoupling protein 2 (UCP2) in beta cells to affect insulin secretion. Regulation of UCP2 by Sirt1 may also be an important axis that is dysregulated by excess fat to contribute to obesity induced diabetes [10].

Sirt1 is a positive regulator of liver X receptor (LXR) proteins [11, 12], nuclear receptors that function as cholesterol sensors and regulate whole-body cholesterol and lipid homeostasis. LXR acetylation is evident at a single conserved lysine (K432 in LXRα and K433 in LXRβ) adjacent to the ligand-regulated activation domain AF2 [2]. Sirt1 interacts with LXR and promotes deacetylation and subsequent ubiquitination. Mutations of K432 eliminate activation of LXRα by this sirtuin [11]. Loss of Sirt1 in vivo reduces expression of a variety of LXR targets involved in lipid metabolism, including ABCA1, an ATP-binding cassette (ABC) transporter that mediates an early step of HDL biogenesis [2, 11]. Altogether these findings suggest that deacetylation of LXRs by Sirt1 may be a mechanism that affects atherosclerosis and other aging-associated diseases [11].

Above information suggests that Sirt1 is involved in regulation of obesity-associated metabolic diseases through regulating PGC-1α, UCP2 and LXR proteins.

Cancer and Sirt1

It has been shown that Sirt1 is significantly elevated in human prostate cancer [13], acute myeloid leukemia [14], and primary colon cancer [15]. Overexpression of Sirt1 was frequently observed in all kinds of non-melanoma skin cancers including squamous cell carcinoma, basal cell carcinoma, Bowen's disease, and actinic keratosis [16]. Based on the elevated levels of Sirt1 in cancers, it was hypothesized that Sirt1 serves as a tumor promoter [17]. The first evidence of Sirt1 as a tumor promoter came from experiments showing that Sirt1 physically interacts with p53 and attenuates p53-mediated functions through deacetylation of p53 at its C-terminal Lys382 residue [18, 19]. In addition, two recent studies demonstrated that DBC1 (deleted in breast cancer-1), which was initially cloned from a region (8p21) homozygously deleted in breast cancer, forms a stable complex with Sirt1 and inhibits Sirt1 activity, leading to increased levels of p53 acetylation and upregulation of p53-mediated function. Consistently, knockdown of DBC1 by RNA interference (RNAi) promoted Sirt1 mediated deacetylation of p53 and inhibited p53-mediated apoptosis induced by genotoxic stress. These effects were reversed in cells by concomitant RNAi-mediated knockdown of endogenous Sirt1 [20, 21]. Sirt1 is also involved in epigenetic silencing of DNA-hypermethylated tumor suppressor genes (TSGs) in cancer cells (Figure 1). Inhibition of Sirt1 by multiple approaches (pharmacologic, over expression of a dominant negative protein or short interfering RNA) leads to TSG re-expression and a block in tumor-causing networks of cell signaling that are activated by loss of the TSGs in a wide range of cancers. Furthermore, Sirt1 inhibition causes re-expression of the E-cadherin gene (in breast and colon cancer cell lines), whose protein product complexes with β-catenin, and this gene reactivation collectively may suppress the constitutive activation of the WNT signaling pathway [22]. Sirt1 acts as a critical modulator of endothelial angiogenic functions. Inhibition of endogenous Sirt1 gene expression prevents the formation of a vascular-like network in vitro. Overexpression of wild-type Sirt1, but not of a deacetylase-defective mutant of Sirt1 (Sirt1 H363Y) [18, 19], increased the sproutforming and migratory activity of endothelial cells [23].

Cell Sci. 2010 February 15; 123(4): 578–585.
Published online 2010 January 26. doi:  10.1242/jcs.060004
PMCID: PMC2818195
Degradation of an intramitochondrial protein by the cytosolic proteasome
Vian Azzu1 and Martin D. Brand1,2,


Mitochondrial uncoupling protein 2 (UCP2) is implicated in a wide range of pathophysiological processes, including immunity and diabetes mellitus, but its rapid degradation remains uncharacterized. Using pharmacological proteasome inhibitors, immunoprecipitation, dominant negative ubiqbiquitiuitin mutants, cellular fractionation and siRNA techniques, we demonstrate the involvement of the ubiquitin-proteasome system in the rapid degradation of UCP2. Importantly, we resolve the issue of whether intramitochondrial proteins can be degraded by the cytosolic proteasome by reconstituting a cell-free system that shows rapid proteasome-inhibitor-sensitive UCP2 degradation in isolated, energised mitochondria presented with an ATP regenerating system, ubiquitin and 26S proteasome fractions. These observations provide the first demonstration that a mitochondrial inner membrane protein is degraded by the cytosolic ubiquitin-proteasome system.


The proteasome is a cytosolic multicatalytic protein degradation system involved in concerted degradation pathways in the cell, including those for the proteolysis of cytosolic, endoplasmic reticulum (Klausner and Sitia, 1990) and mitochondrial outer membrane proteins (Neutzner et al., 2007). This proteolytic pathway is largely, but not solely, mediated by the regulated recognition of proteins and the addition of polyubiquitin chains, which target proteins for proteasomal destruction (Chau et al., 1989; Murakami et al., 1992). One proteasomal pathway that has not convincingly been shown is the degradation of intramitochondrial proteins that are not directly in contact with the cytosol. To date, no mitochondrial protein export machinery has been identified, raising the question of how intramitochondrial proteins could be accessed by a cytosolic degradation machinery given the ostensible barrier of the outer membrane. Here, we identify uncoupling protein 2 (UCP2) as an example of a mitochondrial inner membrane protein that is degraded by this unusual pathway.

UCP2 regulates the bioenergetics of diverse mammalian tissues including the kidney, spleen, pancreas and central nervous system (Brand and Esteves, 2005; Mattiasson and Sullivan, 2006). UCP2 has a broad distribution and is implicated in a variety of processes, including regulation of reactive oxygen species production (Arsenijevic et al., 2000), food intake (Andrews et al., 2008), insulin secretion (Zhang et al., 2001) and immunity (Arsenijevic et al., 2000) as well as pathologies including atherosclerosis (Blanc et al., 2003), cancer (Derdak et al., 2008), diabetes (Zhang et al., 2001) and neuronal injury (Sullivan et al., 2003). UCP2 levels vary dynamically in response to nutrients and this is achieved by varied expression rates against a background of a very short UCP2 protein half-life of ~1 hour (Rousset et al., 2007; Giardina et al., 2008; Azzu et al., 2008). This rapid turnover is not a general result of mitochondrial inner membrane proteolysis or whole mitochondrial turnover by autophagy, since the adenine nucleotide translocase (ANT) — a related carrier also integral to the mitochondrial inner membrane − is not degraded in the same time period. In contrast to the situation in cells, UCP2 is stable in isolated mitochondria, suggesting that extramitochondrial factors may be involved in the UCP2 degradation pathway (Azzu et al., 2008).


Longevity protein may help treat diabetes, cancer, says study


Published Jan 22, 2018, 9:17 am IST
Updated Jan 22, 2018, 9:17 am IST
Named after the Greek goddess who spun the thread of life, Klotho proteins are located on the surface of cells of specific tissues.

The proteins bind to a family of hormones, designated endocrine Fibroblast growth factors (FGFs), that regulate critical metabolic processes in the liver, kidneys, and brain, among other organs. (Photo: Pixabay)
The proteins bind to a family of hormones, designated endocrine Fibroblast growth factors (FGFs), that regulate critical metabolic processes in the liver, kidneys, and brain, among other organs. (Photo: Pixabay)

New York: Scientists have revealed the three-dimensional structure of longevity protein that may help develop therapies to treat diabetes, obesity and certain cancers.

Named after the Greek goddess who spun the thread of life, Klotho proteins are located on the surface of cells of specific tissues.

The proteins bind to a family of hormones, designated endocrine Fibroblast growth factors (FGFs), that regulate critical metabolic processes in the liver, kidneys, and brain, among other organs.

Researchers from Yale University in the US found that beta-Klotho is the primary receptor that binds to FGF21, a key hormone produced upon starvation.

FGF21 stimulates insulin sensitivity and glucose metabolism, causing weight loss. This new understanding of beta-Klotho and FGF21 can guide the development of therapies for conditions such as type 2 diabetes in obese patients, the researchers said.

"Like insulin, FGF21 stimulates metabolism including glucose uptake," said Joseph Schlessinger, from Yale University.

"In animals and in some clinical trials of FGF21, it shows that you can increase burning of calories without changing food intake, and we now understand how to improve the biological activity of FGF21," Schlessinger said.

In the study, published in the journal Nature, the researchers also described a new variant of FGF21 that has 10 times higher potency and cellular activity.

By developing drugs that enhance the pathway, Schlessinger said, researchers can target diabetes and obesity.

(more at link...)


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Post by Cr6 on Sat Mar 31, 2018 12:25 am

Re-defining the problem of how these proteins work in terms of the charge field is important to future working cures. How epi-genetics turn on/off genetic factors with the charge field -- especially with human protein formation ---  is critical to future cures. The randomness and manner in which cells are turned "on/off" as cancerous within the same cancer body...distinctively hints at "charge field" effects with mitochondria.  Overall, this is not too different from the charge field and superconducting with graphene/halogens under pressure.

The Biology of Mitochondrial Uncoupling Proteins

   Sophie Rousset, Marie-Clotilde Alves-Guerra, Julien Mozo, Bruno Miroux, Anne-Marie Cassard-Doulcier, Frédéric Bouillaud and Daniel Ricquier

Diabetes 2004 Feb; 53(suppl 1): S130-S135.


Uncoupling proteins (UCPs) are mitochondrial transporters present in the inner membrane of mitochondria. They are found in all mammals and in plants. They belong to the family of anion mitochondrial carriers including adenine nucleotide transporters. The term “uncoupling protein” was originally used for UCP1, which is uniquely present in mitochondria of brown adipocytes, the thermogenic cells that maintain body temperature in small rodents. In these cells, UCP1 acts as a proton carrier activated by free fatty acids and creates a shunt between complexes of the respiratory chain and ATP synthase. Activation of UCP1 enhances respiration, and the uncoupling process results in a futile cycle and dissipation of oxidation energy as heat. UCP2 is ubiquitous and highly expressed in the lymphoid system, macrophages, and pancreatic islets. UCP3 is mainly expressed in skeletal muscles. In comparison to the established uncoupling and thermogenic activities of UCP1, UCP2 and UCP3 appear to be involved in the limitation of free radical levels in cells rather than in physiological uncoupling and thermogenesis. Moreover, UCP2 is a regulator of insulin secretion and UCP3 is involved in fatty acid metabolism.

ROS, reactive oxygen species
UCP, uncoupling protein

Mitochondria are the cellular organelles where respiration occurs. They contain two compartments bounded by inner and outer membranes. The outer membrane is permeable to small metabolites, whereas the permeability of the inner membrane is controlled to maintain the high electrochemical gradient created by the mitochondrial respiratory chain that is necessary for energy conservation and ATP synthesis in mitochondria. The inner membrane transports anion substrates such as ADP, ATP, phosphate, oxoglutarate, citrate, glutamate, and malate. The reactions of the citric acid cycle, fatty acid oxidation, and several steps of urea synthesis and gluconeogenesis also take place in mitochondria. Energy produced by mitochondrial respiration is used for ATP synthesis by a complex mechanism referred to as “oxidative phosphorylation.” In addition to oxidative phosphorylation and metabolic pathways, mitochondria are involved in thermogenesis, radical production, calcium homeostasis, protein synthesis, and apoptosis. Although respiration is coupled with ADP phosphorylation, this coupling is less than perfect and may be partially or very partially loose. The uncoupling proteins (UCPs) are particular mitochondrial transporters of the inner membrane that appear to be controlling the level of respiration coupling. Several reviews devoted to UCPs have been published in the last few years (1–14). This article is an attempt to summarize recognized as well as putative biological functions of the UCPs.


It has long been known that respiration and mitochondrial ATP synthesis are coupled. The observation that decreased ATP utilization inhibited oxygen consumption and that respiration rate increased when mitochondria synthesized more ATP led to the concept of respiratory control by ADP phosphorylation. In fact, there is a link between mitochondrial ATP synthesis and cellular ATP demand by a feedback mechanism controlling ATP synthesis induced by mitochondrial respiration. After the seminal proposal made by Peter Mitchell (chemi-osmotic theory), it was demonstrated that the mitochondrial electrochemical proton gradient, generated as electrons are passed down the respiratory chain, is the primary source for cellular ATP synthesis. The mitochondrial respiratory chain is made of five complexes. Complexes I, III, and IV pump protons outside the inner membrane during reoxidation of coenzymes and generate a proton gradient that is consumed by complex V, which catalyzes ATP synthesis (Fig. 1). In addition to reentry of protons through ATP synthase, a proton leak represents another mechanism consuming the mitochondrial proton gradient. Mitchell’s theory predicted that any proton leak not coupled with ATP synthesis would provoke uncoupling of respiration and thermogenesis. A well-known example of such an uncoupling of respiration to ADP phosphorylation is represented by the mitochondrial uncoupling protein of brown adipocytes (UCP1), which dissipates energy of substrate oxidation as heat (15–18). Besides adaptive thermogenesis, uncoupling of respiration allows continuous reoxidation of coenzymes that are essential to metabolic pathways. In fact, partial uncoupling of respiration prevents an exaggerated increase in ATP level that would inhibit respiration.


Morphologists and physiologists identified the brown adipose tissue as a particular form of adipose tissue in hibernators and small mammals and observed its thermogenic activity in infants at birth, rodents exposed to the cold, and hibernators during arousal (15–17). Brown adipocytes differ from white adipocytes by a direct sympathetic innervation, a central nucleus, many triglyceride droplets, and numerous mitochondria. Original studies of isolated brown fat mitochondria revealed an elevated respiratory rate and an uncoupled respiration not controlled by ADP. A rapid respiration not coupled with ATP synthesis represents a powerful thermogenic process. It was also established that activation of brown adipocytes by norepinephrine was immediately followed by increased respiration and heat production, a marked increase in blood flow, and evacuation of warmed blood toward the brain and cardiac regions. It appeared that fatty acids generated by stimulated lipolysis were directly activating a specific proton pathway not coupled with ADP phosphorylation in the inner mitochondrial membrane. The protein explaining this proton pathway was identified as a 33-kDa UCP (15–18). Brown fat mitochondrial UCP is unique to brown adipocytes. The UCP content reflects the thermogenic activity of brown fat deposits: the elevated thermogenic capacity of brown fat of rats adapted to cold parallels the increased UCP in mitochondria. Decrease in brown fat thermogenic capacity during postnatal development in many mammals is accompanied by a declining UCP content. The brown fat UCP belongs to the family of the anion carriers present in the inner membrane of mitochondria. Like the mitochondrial adenine nucleotide transporters, the phosphate carrier, or the citrate carrier, UCP has a triplicate structure and every third is made of two transmembrane domains attached by a more hydrophilic domain (Fig. 2).

Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) F1.medium
FIG. 1.

The mitochondrial proton gradient generated by complexes of respiratory chain is used by F0-F1-ATP synthase to phosphorylate ADP. Another mechanism consuming the gradient and lowering ATP synthesis is proton leak (yellow arrow). The reentry of protons in the matrix noncoupled with ATP synthesis is an energy-dissipating mechanism. The brown fat UCP1 is an example of mitochondrial proton leak. Cyt C, cytochrome C; ΔμH+, proton electrochemical gradient; e−, electron; F0, membranous part of ATP-synthase; F1, catalytic part of ATP-synthase.
(more at link...)


   ↵Garlid KD, Jaburek M: The mechanism of proton transport mediated by mitochondrial uncoupling proteins. FEBS Lett438 :10 –14,1998
   OpenUrlCrossRefPubMedWeb of Science
   ↵Diehl AM, Hoek JB: Mitochondrial uncoupling: role of uncoupling protein anion carriers and relationship to thermogenesis and weight control “The benefits of losing control.” J Bioenerg Biomembr31 :493 –505,1999
   OpenUrlCrossRefPubMedWeb of Science
   ↵Ricquier D, Miroux B, Cassard-Doulcier AM, Lévi-Meyrueis C, Gelly C, Raimbault S, Bouillaud F: Contribution to the identification and analysis of the mitochondrial uncoupling proteins. J Bioenerg Biomembr31 :407 –418,1999
   Kozak LP, Harper ME: Mitochondrial uncoupling proteins in energy expenditure. Annu Rev Nutr20 :339 –363,2000
   OpenUrlCrossRefPubMedWeb of Science
   ↵Ricquier D, Bouillaud F: The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Biochem J345 :161 –179,2000
   Boss O, Hagen T, Lowell BB: Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. Diabetes49 :143 –156,2000


Tuesday, 4 March 2014

The role of UCP2 & UCP4 in stem cells

An embryonic stem cell differentiating into a neuronal cell under the microscope.

Credit: Anne Rupprecht/Vetmeduni Vienna

Cells have a metabolism that can be altered according to its function and requirements. If cellular metabolism is disturbed, it can lead to disease of the entire organism. Now, researchers at the University of Veterinary Medicine in Vienna say that they have discovered that the uncoupling proteins UCP2 and UPC4 are involved in different types of cellular metabolism.

The proteins provide information about the condition of cells. As a result, cell alterations can now be detected much earlier than it was previously possible.

UCPs or uncoupling proteins are present in mitochondria, the powerhouses of each cell in our body. The functions of most of the five known UCPs remain mysterious (UCP2-UCP5), whereby only the distinct function for UCP1 has thus far been discovered. UCP1 is responsible for heat production when muscle activity is deficient such as is the case with babies and animals in hibernation.

The researchers at the Department of Physiology and Biophysics at the University of Veterinary Medicine in Vienna were able to provide a fundamental explanatory concept for the function of UCP2 and UPC4 for the first time. Each of these proteins are involved in different types of cell metabolism.

UCP2 in Stem Cells and Cancer Cells

In earlier studies of immune cells, lead author, Anne Rupprecht, had already shown that UCP2 could be involved in increased metabolism. Embryonic stem cells (ESCs), precisely exhibit such an increased metabolism, as they rapidly and continually divide, just like cancer cells. Rupprecht searched for various UCPs in  ESCs of mice and in effect found UCP2. "Very high amounts of UCP2 even indicated an especially strong increase in metabolism. In other studies UCP2 had also already been detected in cancer cells," according to Rupprecht.

UCP4 in Nerve Cells

In contrast to UCP2, UCP4 is only found in nerve cells. Nerve cells have a completely different metabolism. They seldom divide, unlike stem cells and cancer cells. The research team of Prof. Elena Pohl therefore examined ESCs that differentiated to nerve cells in culture. On the basis of this model system, the researchers could show that UCP2 is still existent in the quickly reproducing stem cells, yet at the moment of differentiation are replaced by UPC4.

   "In our work, we have examined the natural process of cell differentiation from stem cells to neurons. We know that metabolism changes during differentiation. The fact that we found UCP2 in one case and in the other UCP4 proves for the first time that these proteins are associated with varying types of cell metabolism." said Elena Pohl.

The researchers, for example, found only UCP2 in neuroblastoma cells -- nerve cells that have malignant changes. UCP4, the usual protein of nerve cells was not detectable. UPC4 apparently got lost in the changed nerve cells that were on their way to becoming rapidly reproductive cancer cells.

(more at link....)


Superoxide-mediated activation of uncoupling protein 2 causes pancreatic β cell dysfunction

Stefan Krauss,1 Chen-Yu Zhang,1 Luca Scorrano,2 Louise T. Dalgaard,1 Julie St-Pierre,3 Shane T. Grey,4 and Bradford B. Lowell1

First published December 15, 2003 - More info

See the related Commentary beginning on page 1788.


   Failure to secrete adequate amounts of insulin in response to increasing concentrations of glucose is an important feature of type 2 diabetes. The mechanism for loss of glucose responsiveness is unknown. Uncoupling protein 2 (UCP2), by virtue of its mitochondrial proton leak activity and consequent negative effect on ATP production, impairs glucose-stimulated insulin secretion. Of interest, it has recently been shown that superoxide, when added to isolated mitochondria, activates UCP2-mediated proton leak. Since obesity and chronic hyperglycemia increase mitochondrial superoxide production, as well as UCP2 expression in pancreatic β cells, a superoxide-UCP2 pathway could contribute importantly to obesity- and hyperglycemia-induced β cell dysfunction. This study demonstrates that endogenously produced mitochondrial superoxide activates UCP2-mediated proton leak, thus lowering ATP levels and impairing glucose-stimulated insulin secretion. Furthermore, hyperglycemia- and obesity-induced loss of glucose responsiveness is prevented by reduction of mitochondrial superoxide production or gene knockout of UCP2. Importantly, reduction of superoxide has no beneficial effect in the absence of UCP2, and superoxide levels are increased further in the absence of UCP2, demonstrating that the adverse effects of superoxide on β cell glucose sensing are caused by activation of UCP2. Therefore, superoxide-mediated activation of UCP2 could play an important role in the pathogenesis of β cell dysfunction and type 2 diabetes.


Summary of Berberine

Primary Information, Benefits, Effects, and Important Facts

Berberine is an alkaloid extracted from various plants used in traditional Chinese medicine.

Berberine is supplemented for its anti-inflammatory and anti-diabetic effects. It can also improve intestinal health and lower cholesterol. Berberine is able to reduce glucose production in the liver. Human and animal research demonstrates that 1500mg of berberine, taken in three doses of 500mg each, is equally effective as taking 1500mg of metformin or 4mg glibenclamide, two pharmaceuticals for treating type II diabetes. Effectiveness was measured by how well the drugs reduced biomarkers of type II diabetes.

Berberine may also synergize with anti-depressant medication and help with body fat loss. Both of these benefits need additional evidence behind them before berberine can be recommended specifically for these reasons.

Berberine’s main mechanism is partly responsible for its anti-diabetic and anti-inflammatory effects. Berberine is able to activate an enzyme called Adenosine Monophosphate-Activated Protein Kinase (AMPK) while inhibiting Protein-Tyrosine Phosphatase 1B (PTP1B).

Berberine has a high potential to interact with a medications, and some interactions may be serious.

Berberine is one of the few supplements in the database with human evidence that establishes it to be as effective as pharmaceuticals.

(NOT ADVOCATING THIS...just found it interesting....)

Get Metformin-Like AntiCancer Activity Without A Prescription (Berberine)

Feb 23, 2013 Brian D. Lawenda, M.D.

Huang Lian

What Is Berberine?

Berberine is one of the active alkaloid extracts, derived from a variety of plants (i.e. Oregon grape, barberry, tree turmeric, goldenseal, Amor cork tree, Chinese goldthread or “huanglian” or “Coptis chinensis”, etc.), that have been traditionally used in Ayurvedic and Chinese medicines for the treatment of diabetes, infections and gastrointestinal problems.

Studies* have demonstrated a wide-range of benefits of berberine:

*(human, in-vivo and/or  in-vitro)
   liver protection (protects against chemotherapy injury)
   anti-Alzheimer’s disease
   anti-rheumatoid arthritis
   anti-diabetic  (randomized trial found that berberine is as effective as the drug metformin); that should be no surprise, as berberine has many of the same effects as metformin (i.e. AMP kinase activator, increases insulin sensitivity, decreases gluconeogenesis, reduces glucose absorption in the gut, etc.)…so, if your physician won’t write you that prescription for metformin for its’ anti-cancer benefits, maybe berberine is a good alternative. (Read more about metformin on my prior blog post)
   anti-cancer (causes cancer cell death, slows cancer growth and increases the effectiveness of radiation therapy and chemotherapy)
   Inhibits the development of cancer from carcinogen exposure
   promotes weight loss
   cholesterol & triglyceride lowering (in one randomized study: lowering triglycerides by 36%, LDL cholesterol by 21%, and total cholesterol by 18%)
   improves post-operative ileus
   protects against radiation-induced gastrointestinal symptoms (this study used a dose of 300 mg, three-times per day during radiation therapy)
   reduces colitis

How Does It Work?

It slows cancer growth and causes cancer cell death through a variety of mechanisms: tumor cell apoptosis and cell cycle arrest, inhibits blood vessel growth to tumors, inhibition of tumor cellular invasion and metastases (spread), etc.

One of the main anti-cancer targets that is inhibited by berberine is NF-kappaB. NF-kappa B is one of the most important proteins in our cells, acting as a key switch in the development and progression of inflammation and cancer.

  •   Cancer (and precancerous cells) often have a permanently activated NF-kappa B, which keeps the cells proliferating and prevents them from dying (apoptosis.)
       Chronic inflammation can also be a result of activated NF-kappa B, and we know that chronic inflammation can lead to cancer growth (learn more about this on my previous blog post.)

Additionally, berberine is a radio-sensitizer of tumor cells, but not of normal cells (in fact, it may protect normal cells.) Therefore, berberine may make radiation therapy more effective.

Berberine also inhibits the tendency of cancer cells to become drug resistant over time by inhibiting the cellular membrane proteins that pump drugs out of the cell.

When berberine is taken with numerous chemotherapy drugs, studies have shown that they work synergistically against cancer cells.

As with other promising anti-cancer plant compounds (i.e. green tea, turmeric, etc.), there are data suggesting that using the whole plant extract (Coptidis rhizoma or “huanglian”) may be more effective than simply taking berberine, alone. This is potentially due to synergistic effects of the many known and unknown anti-cancer compounds in the whole plant.

   Displaces bilirubin and should not be administered to jaundiced neonates (may increase bilirubin levels due to displacement of bilirubin from albumin)
   May cause a prolonged QT interval (a variable in cardiac electrical conduction) in patients with underlying heart disease

Herb-Drug Interactions

   Berberine inhibits liver enzymes called “cytochromes P450“ (specifically these enzymes: CYP2D6, CYP2D6, CYP2C9, and CYP3A4): taking a drug or supplement that also inhibits these liver enzymes can increase the blood levels of both compounds, increasing the risk of toxicity.
   Always discuss your use of supplements with your physicians first, before starting them.
   Here’s an abbreviated list of some of the more common drugs that also interact with the cytochromes p450 enzymes.

(Reputed Cyc-C interactions)

Cancer and Berberine

There is an inflammatory enzyme called cyclooxygenase-2 (COX-2) that is abundantly expressed in colon cancer cells. It also plays a key role in colon tumorigenesis (new cancer growth). Therefore, compounds inhibiting COX-2 transcriptional activity (gene RNA replication) potentially have a chemopreventive property. Finding natural compounds to inhibit COX-2 pathways should prove exciting and promising.

In a recent study, an assay method for estimating COX-2 transcriptional activity in human colon cancer cells was established using a β-galactosidase reporter gene system. The study examined effects made of various medicinal herbs and their ingredients for an inhibitory effect on COX-2 transcriptional activity.

They found that berberine, an isoquinoline alkaloid present in plants of the genera Berberis and Coptis from Oregon grape root and Bayberry, effectively inhibits COX-2 transcriptional activity in colon cancer cells in a dose- and time-dependent manner at concentrations higher than 0.3 μM. These findings may further explain the mechanism of anti-inflammatory and anti-tumor promoting effects of berberine.

Berberine and Breast Cancer

Berberine has many other biological activities including the ability to induce cell cycle arrest and apoptosis, making it a potentially useful agent for targeting cancer cells other than just the colon. Another study analyzed the effects of berberine on MCF-7 breast cancer cells. Berberine was added to MCF-7 cells in culture, and proliferation, side population (SP) cells and expression of ABCG2 were examined resulting in very promising results:

1. Berberine caused a dose-dependent reduction in proliferation (new cancer growth).
2. Berberine treatment caused a decrease in SP cells (cells that become circulating tumor cells or cancer stem cells) relative to untreated controls.
3. In addition, berberine treatment was associated with a decrease in expression of ABCG2 relative to untreated controls (ABCG2 expression is associated with increased resistance to chemotherapeutic agents).

These results indicate that the growth inhibitory effects of berberine treatment on MCF-7  Cancer cells may be reason in itself for use.
Berberine limits Metastasis and Angiogenesis

Metastasis and angiogenesis is to be avoided at all cost. There is increasing evidence that two chemicals, urokinase-type plasminogen activator (u-PA) and matrix metalloproteinases (MMPs) play an important role in cancer spread and vasculization. Inhibition of u-PA and MMPs could suppress migration and invasion of cancer cells. Berberine reported to have anti-cancer effects in different human cancer cell lines by inhibiting u-PA and MMPs according to another study.

The treatment of human prostate cancer cells (PC-3) with berberine was shown to induce dose-dependent apoptosis.   Berberine-induced apoptosis was associated with the disruption of the mitochondrial membrane potential, release of apoptogenic molecules (cytochrome c and Smac/DIABLO) from mitochondria and cleavage of caspase-9,-3 and PARP proteins. In xenograft in vivo studies, berberine reduced tumor weights and volumes accompanied with apoptotic cell death and increased expression of apoptotic cell death proteins.

   Berberine can stimulate a Th1 reaction so use with caution.

(more at link...)


Berberine hydrochloride: anticancer activity and nanoparticulate delivery system

Wen Tan, Yingbo Li, Meiwan Chen, and Yitao Wang
Author information ► Copyright and License information ► Disclaimer
This article has been cited by other articles in PMC.



Berberine hydrochloride is a conventional component in Chinese medicine, and is characterized by a diversity of pharmacological effects. However, due to its hydrophobic properties, along with poor stability and bioavailability, the application of berberine hydrochloride was hampered for a long time. In recent years, the pharmaceutical preparation of berberine hydrochloride has improved to achieve good prospects for clinical application, especially for novel nanoparticulate delivery systems. Moreover, anticancer activity and novel mechanisms have been explored, the chance of regulating glucose and lipid metabolism in cancer cells showing more potential than ever. Therefore, it is expected that appropriate pharmaceutical procedures could be applied to the enormous potential for anticancer efficacy, to give some new insights into anticancer drug preparation in Chinese medicine.
Methods and results

We accessed conventional databases, such as PubMed, Scope, and Web of Science, using “berberine hydrochloride”, “anti-cancer mechanism”, and “nanoparticulate delivery system” as search words, then summarized the progress in research, illustrating the need to explore reprogramming of cancer cell metabolism using nanoparticulate drug delivery systems.


With increasing research on regulation of cancer cell metabolism by berberine hydrochloride and troubleshooting of issues concerning nanoparticulate delivery preparation, berberine hydrochloride is likely to become a natural component of the nanoparticulate delivery systems used for cancer therapy. Meanwhile, the known mechanisms of berberine hydrochloride, such as decreased multidrug resistance and enhanced sensitivity of chemotherapeutic drugs, along with improvement in patient quality of life, could also provide new insights into cancer cell metabolism and nanoparticulate delivery preparation.
Keywords: berberine hydrochloride, anticancer mechanisms, nanoparticulate drug progress


Berberine hydrochloride is an isoquinoline alkaloid (see Figure 1) isolated from a variety of Chinese herbs, including Coptidis rhizoma, Phellodendron chinense schneid, and Phellodendron amurense, and has diverse pharmacological actions. It has antidiabetic and antilipid peroxidation activity, as well as an anti-atherosclerotic action, and also has neuroprotective properties and improves polycystic ovary syndrome.1–5 Berberine hydrochloride is widely used as an antibacterial, antifungal, and anti-inflammatory drug, and has been used as a gastrointestinal remedy for thousands of years in China.6,7

(more at link...)


Molecules 2014, 19(Cool, 12349-12367; doi:10.3390/molecules190812349

Berberine, an Epiphany Against Cancer

Luis Miguel Guamán Ortiz 1,2, Paolo Lombardi 3, Micol Tillhon 1 and Anna Ivana Scovassi 1,*1
Istituto di Genetica Molecolare CNR, Via Abbiategrasso 207, Pavia 27100, Italy2
Departamento de Ciencias de la Salud, Universidad Técnica Particular de Loja, San Cayetano Alto, Calle París, Loja 1101608, Ecuador3
Naxospharma, Via Giuseppe di Vittorio 70, Novate Milanese 20026, Italy*
Author to whom correspondence should be addressed; Tel.: +39-0382-546-334; Fax: +39-0382-422-286.
Received: 27 June 2014; in revised form: 6 August 2014 / Accepted: 11 August 2014 / Published: 15 August 2014

Alkaloids are used in traditional medicine for the treatment of many diseases. These compounds are synthesized in plants as secondary metabolites and have multiple effects on cellular metabolism. Among plant derivatives with biological properties, the isoquinoline quaternary alkaloid berberine possesses a broad range of therapeutic uses against several diseases. In recent years, berberine has been reported to inhibit cell proliferation and to be cytotoxic towards cancer cells. Based on this evidence, many derivatives have been synthesized to improve berberine efficiency and selectivity; the results so far obtained on human cancer cell lines support the idea that they could be promising agents for cancer treatment. The main properties of berberine and derivatives will be illustrated.

apoptosis; autophagy; berberine; cancer; traditional medicine

1. Introduction

Natural compounds have been used for centuries because of their availability; those present in plants are employed in the so-called Traditional Medicine, which translates theories, beliefs and experiences into knowledge, skills and practices applied to prevent, diagnose and treat physical and mental disorders [1]. Being recognized as an integral part of the culture and traditions of populations, Traditional Medicine has been recommended by the World Health Organization as an effective complementary and alternative medicine for different diseases [2].

Plants have wide biological and medicinal properties, and are characterized by high safety, availability, accessibility and low cost, thus representing an invaluable source of chemicals with potential therapeutic effects [3,4]. Secondary metabolites of plants, such as flavonoids, saponins, tannins, steroids and alkaloids, display a number of properties, including hormonal mimicry, antioxidant, antibacterial, anti-inflammatory, immunomodulating, detoxificant effects [5] and even anticancer activity [3,4,6].

2. Berberine

Among the several plant secondary metabolites, alkaloids possess a variety of pharmacological properties. Berberine (BBR, C20H19NO5, Figure 1, a 5,6-dihydro-dibenzo[a,g]quinolizinium derivative) is an isoquinoline quaternary alkaloid isolated from many kinds of medicinal plants such as Hydrastis canadensis, Berberis aristata, Coptis chinensis, Coptis japonica, Phellondendron amurense and Phellondendron chinense Schneid [7,8]. BBR has antioxidant effects and multiple pharmacological properties. It has been found to be effective against gastroenteritis, diarrhea, hyperlipidemia, obesity, fatty liver and coronary artery diseases, hypertension, diabetes and metabolic syndrome, polycystic ovary [8,9,10,11] and Alzheimer’s disease [12,13]. Recently, in vitro studies using cancer cell lines have shown that BBR inhibits cancer cell proliferation and migration, and induces apoptosis in a variety of cancer cell lines [8,14,15,16], stimulating further development of derivatives for drug-base cancer prevention and treatment.

Many groups are actively working to depict the molecular mechanism of action of BBR; although many results suggest that the molecular structure of BBR is able to bind DNA, other nuclear and cytoplasmic targets have been identified (see below).
Molecules 19 12349 g001 1024
Figure 1. Chemical structure of berberine chloride.

3. Molecular Targets of Berberine

BBR interacts directly with nucleic acids and with several proteins, including telomerase, DNA topoisomerase I, p53, NF-kB, MMPs and estrogen receptors. In general, BBR treatment promotes cell cycle arrest and death in human cancer cell lines, coupled to an increased expression of apoptotic factors [8,15,16]. The main known targets of BBR are below described.

4. Berberine and Cancer

The search for new drugs that induce apoptosis in tumors refractory to the conventional therapy is crucial to develop efficient anticancer therapies. Several mechanisms by which BBR inhibits the proliferation of different cancer cell lines have been reported. Among them, the killing of cancer cells by the activation of apoptosis is the best characterized.

In this context, several groups have reported the pro-apoptotic effect of BBR mediated by the impact on mitochondria. In fact, BBR was proved to alter the mitochondrial membrane potential (MMP), inhibit mitochondrial respiration leading to mitochondrial dysfunction and regulate the expression of Bcl-2 family members, as Mcl-1 [45,47]. Alterations in mitochondrial membrane stimulate the release of cytochrome c promoting the formation of reactive oxygen species (ROS) that trigger apoptosis that requires the activation of caspases and poly(ADP-ribose) polymerase-1 (PARP-1) cleavage [64]. Some examples of the pro-apoptotic effect of BBR are shown in Table 1 (see references therein).
Table 1. Examples of the multiple effects of BBR leading to apoptosis in different cancer cell lines.

BBR pro-apoptotic effects could be mediated through the modulation of the HER2/PI3K/Akt [71,72] and/or JNK/p38 signaling pathway [76] an impact of BBR on the NF-kB pathway, leading to inactivation of this factor with consequent triggering of the apoptotic process, cell cycle and invasion pathway arrest, was reported [85]. The inhibition of the transcription factor AP-1 by BBR caused apoptosis in human hepatoma [86], oral [87], breast [88] and colon [89] cancer cells.

BBR modulates the activity of the Bcl-2 family members; increased expression of pro-apoptotic protein Bax (Bcl-2-associated X protein) together with decrease of Bcl-2/Bcl-xL after BBR treatment was observed not only in human prostate epithelial (PWR-1E) or carcinoma cells (DU145, PC-3 and LNCaP), but also in promyelocytic leukemia, gastric carcinoma and lung cancer cells, inducing cell death (Table 1).

Caspase-dependent apoptosis was reported in colon carcinoma cells treated with 13-arylalkyl BBR derivatives [33]. BBR has been used to treat TRAIL-sensitive breast cancer cells, and found to be able to sensitize also TRAIL-resistant breast cancer cells to apoptosis [48,49]. BBR suppresses HPV transcription in dose and time dependent manner in cervical cancer cell lines [84].

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