Turning Off the Cancer Switch
by Bill Sardi
Recently by Bill Sardi: April 28, 2004: A Disastrous Day for the American Economy
Cancer researchers now recognize that molecular signals sent to healthy cells can convert them to tumor cells and that blockage of these "cancer signals" may put an abrupt halt to tumor growth.
Researchers now think they have found the precise molecular switch that "turns on" cancer, and this suggests an antidote to cancer may soon be at hand.
The Warburg Effect — you mean that eight-decades-old research conducted by German biochemist Otto Warburg, for which he was awarded a Nobel Prize in 1931? This means cancer researchers may have actually lost ground in their war against cancer by largely dismissing Warburg’s observations first reported in 1926.
What Warburg unequivocally demonstrated was that while healthy cells, in order to survive, burn up oxygen to create cellular energy, cancer cells convert to utilizing sugar to produce energy.
In Otto Warburg’s lecture entitled "Prime cause and prevention of cancer" he stated: "Oxygen gas, the donor of energy in plants and animals, is dethroned in the cancer cells and replaced by an energy yielding reaction of the lowest living forms, namely, fermentation of glucose (sugar)."
The National Library of Medicine currently lists 290 published reports about The Warburg Effect since 1931 — 115 of them published in 2007-08-09. There certainly is a resurgence of interest in Warburg’s demonstration that tumors have a sweet tooth. The journal Science named cancer metabolism as an area to watch in 2010 and the American Association for Cancer Research recently hosted a 4-day meeting on cancer and metabolism.
But it wasn’t just conventional medicine that got side-tracked by Warburg’s discovery. In "the Warburg Effect," tumor cells expel lactic acid as a by-product, and this later became known as the alkalinity-acidity theory of cancer promoted by many pseudo-scientists. This spawned a number of books that mistakenly advocated an alkaline diet would cure or prevent cancer. Actually, cancer cells are a bit more acid immediately outside their boundaries than inside due to the expelling of lactic acid.
The pursuit of a state of alkalinity appears to be nonsensical. Not only does the absence of acidity in the gastric tract and bladder establish an environment that is conducive to tumor growth, the control of blood pH (alkalinity/acidity) is automatically controlled in a neutral pH range (7.2—7.4). The diet has little influence over the pH of the blood.
In 1987 an experiment was conducted where the effects of alkalinity or acidity were examined in bladder cancer. Animals were fed a diet that was somewhat acidic, mildly alkaline or more alkaline. Bladder tumors occurred in 39% of the acidic group, 65% of the alkaline group and 71% of the more alkaline group.
Many alternative medical practitioners inexplicably recommend acid-forming supplements (Lactobacillus acidophilus) for cancer patients, yet they contrarily suggest an alkaline diet. An experiment conducted in 1980 showed that the provision of acid-forming bacteria (Lactobacillus acidophilus) reduced chemically-induced colon cancer in animals from 77% to 40%. Enough said about misdirection since Warburg’s discovery.
Reconsideration of the Warburg Effect
Cancer researchers say they began to reconsider Warburg’s claims when two recently published papers identified a key enzyme shift required for The Warburg Effect to occur. The enzyme M1-pyruvate kinase (M1-PK) in healthy cells shifts to M2-pyruvate kinase (M2-PK) in tumor cells.
In the first study, the PK-M2 enzyme was shown to be necessary to turn normal cells into tumor cells. In the second study, researchers not only said they found "a single switch in a form of an enzyme pyruvate kinase (PK M2) is necessary for the shift in cellular metabolism that … promotes tumors," but they also employed RNA to reverse the Warburg effect and produced only the M1-PK enzyme in tumor cells, which leads to reduced ability to form tumors in mice. Both studies were published in 2008.
There is already a test kit available for M2-PK (ScheBo Biotech AG, Giessen, Germany) for bowel cancer screening and it is fairly reliable — the test is able to detect between 73 and 97 of every 100 patients who have colon or rectal cancer. So cancer doctors can begin testing for the presence of this enzyme.
The search for PK-M2 inhibitors
Cancer researchers are in hot pursuit of small molecules that can enter tumor cells and inhibit the PK-M2 enzyme. Over 1 million such molecules were recently screened for their ability to inhibit PK-M2. At low concentration, 74 of these molecules were found to specifically inhibit PK-M2, proving that it is feasible to block conversion of normal cells to tumor cells. Unfortunately, the researchers involved in this study aren’t disclosing to the world the identity of those 74 molecules. Many of them are anticipated to be currently available drugs or natural molecules that could be obtained in dietary supplements.
These researchers do reveal, unsurprisingly, that a class of sugar-controlling molecules called thiazolidinediones — which includes the anti-diabetic drugs rosiglitazone (Avandia) and pioglitazone (Actos), exhibit strong inhibition of the PK-M2 enzyme.
However, the suitability of this class of molecules for cancer treatment is in question given concerns over increased risk for heart-related side effects. Another anti-diabetic drug (Rezulin), in the same class as Avandia and Actos, has already been recalled by the FDA. Avandia and Actos now carry black-box warnings about cardiac risks and require repeated liver testing. The use of thiazolidinediones for cancer treatment may be trading one mortal disease for another.
The problem here is that researchers, in their quest to develop a profitable anti-cancer drug, will take years to agonizingly obtain approval for PK-M2 inhibitors while cancer patients are desperate for a cure. A financially strapped health insurance system is on the verge of collapse. The pursuit of yet more expensive pharmacologic cures appears to be misdirected towards profiteering rather than curing. There may be simpler and more economical ways to address sugar’s role in cancer growth.
Another class of small molecules, found in nature within pomegranates, grapes, berries, olives, tea leaves and certain spices, called polyphenols, are widely known as enzyme inhibitors and inhibitors of glucose metabolism.
Two of these natural molecules, quercetin (pronounced kwer-see-tin), which has been shown to produce 80% inhibition of lactic acid at high concentration, and resveratrol (pronounced rez-vair-aw-trawl), have already been demonstrated to significantly inhibit lactate production and the growth of tumor cells. They are available as dietary supplements.
Researchers indicate more potent PK-M2 inhibitors may be needed to produce a therapeutic effect for cancer. Maybe natural PK-M2 inhibitors do not significantly inhibit PK-M2.
However, this year (2009) it was found that the combination of low doses of resveratrol or quercetin have no effect upon cancer cell death when used individually, but that when combined these two molecules exert strong synergistic effect that arrests tumor cell growth. Even more surprising was a study where three natural small molecules, resveratrol, quercetin and IP6 from rice bran were added to the diet of laboratory mice and slowed the age-related conversion of cell energy to sugar in laboratory mice heart tissue at a relatively low dose, and exerted this change far earlier than a calorie-restricted diet. So it cannot be said that cancer patients should necessarily wait for pharmaceutical versions of PK-M2 inhibitors.
However, there is concern that over-inhibition of glycolysis (the conversion of glucose to pyruvate) could starve tissues in the brain, retina and nervous system that have high demand for sugar, which could be harmful. Modest-to-strong inhibition of PK-M2 may be more desirable when combined with other therapies.
Another concern is that, deprived of sugar, tumor cells will find alternate ways to produce energy, most likely from fats. But here again nature’s pharmacy shows its versatility.
Excess glucose can be stored efficiently as fat. Triglycerides, the chemical form in which most fat exists in food as well as in the body, yield more than twice as much energy for the same mass as do carbohydrates or proteins, and can serve as a source of fuel for tumor cells. A combination of green tea molecules, resveratrol and quercetin has been shown to inhibit fatty acid synthase, the enzyme required to store fat in the body. Quercetin plus resveratrol works far better in this regard over use of either molecule alone.
Yet another pathway
The precise mechanisms that cause PK-M1 to convert to PK-M2 have eluded researchers till recently. In November of 2009, researchers reporting in the journal Science Signaling, indicate a process called tyrosine phosphorylation (tie-row-seen fos-for-illay-shun) inhibits PK-M2. Tyrosine is an amino acid. The addition of phosphate to tyrosine is called tyrosine phosphorylation. Phosphate regulates enzymes, turning them on or off.
A number of natural molecules strongly influence tyrosine phosphorylation. Among them, vitamin D is a master hormone/vitamin regulator of tyrosine phosphorylation and has been shown to exhibit anti-cancer effects, particularly via its ability to inhibit the pyruvate kinase enzyme and lactic acid. Quercetin has also been found to inhibit tyrosine phosphorylation.
You won’t hear of any of these natural molecules from your oncologist, but they are among the most promising anti-cancer molecules in existence. Consider the fact that resveratrol blocks cancer at all three stages of development — initiation, growth and spread (metastasis), something no cancer drug can claim. These natural molecules have already been demonstrated to outperform chemotherapy drugs in animal studies. But there is a lot of foot-dragging to conduct human studies.
Oncologists respond that these natural molecular medicine approaches to cancer prevention or treatment are unproven, but we hear no cry to put them to the test. Recognize modern cancer therapies have largely been disproven. While there is treatment for cancer, there are no cures. If there were, so many cancer patients wouldn’t be on an unguided search to find one. Alternative cancer therapies are belittled by conventional medicine when its armamentarium against cancer has a rather limited effect. For example, cancer chemotherapy has been shown to contribute to the 5-year survival of cancer patients only about 2% of the time. Chemotherapy and radiation therapy for cancer cannot penetrate solid tumors and therefore are largely ineffective.
Refined sugar and cancer
Given the recent recognition of Otto Warburg’s discovery involving sugar and cancer, it seems odd that few cancer patients are advised to limit refined sugar intake. A study written by researchers in Italy and published in the International Journal of Cancer in 1993 is instructive. The Italian researchers studied 953 cases of colon cancer and compared them against 2845 healthy control subjects. Compared to individuals who did not add sugar to their beverages, the addition of 1 spoonful of sugar increased the risk of colon cancer by 40%; 2 tablespoons by 60%; the risk doubled for those who added 2 or more tablespoons of sugar to their beverage of choice.
Dr. John T. Ely writes that the limitation of refined sugars may improve survival after cancer has been detected. His investigation found a measure of blood sugar (glycated hemoglobin, called hemoglobin A1c, which is indicative of blood sugar levels over a 2—3 month period of time) and found a significant lower average blood sugar number for patients in cancer remission.
Dr. Ely goes on to provide other convincing evidence:
- In a study of 24 tumor patients, the only ones who achieved sustained remission from their malignancies were the 5 patients whose glucose tolerance improved.
- The effectiveness of conventional radiation for cervical cancer is enhanced several-fold when dietary sugar is prohibited.
- Patients under insulin coma therapy for 6 months (for psychosis) are reported to become free of large tumor burdens considered incurable by their oncologists.
- In an animal model of breast cancer, Dr. Ely showed that mortality correlated with average blood sugar number, that is, the highest average blood sugar resulted in the highest mortality.
Dr. Ely goes on to explain a link between elevated blood sugar and impairment of the human immune system via sugar’s ability to reduce vitamin C concentration in white blood cells. Dr. Ely claims prior studies which showed high-dose oral vitamin C to be ineffective against cancer did not factor for blood sugar levels. For white blood cells (largely neutrophils) to maintain activity against tumor cells they must maintain a high concentration of vitamin C, up to 50-times higher concentration than in blood plasma. As blood sugar levels rise, vitamin C concentration in white blood cells declines markedly, making them sluggish and inactive. Infusion of glucose (sugar) will cause a 50% decline in vitamin C levels in white blood cells within 10—20 minutes. The ability of white blood cells to kill cancer cells is severely limited when blood sugar levels are high and vitamin C intake is low.