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Controlled Amino Acid Therapy: The Cornerstone Article

The following scientific article, "Dysfunctional Mitochondria, not Oxygen Insufficiency, Cause Cancer Cells to Produce Inordinate Amounts of Lactic Acid: The Impact of this on the Treatment of Cancer," by cancer scientist Angelo John, Sr., appears in the October 2001 issue (Volume 57, Number 4, pages 429–31) of the journal Medical Hypotheses.

Summary

It has been known for decades that cancer cells produce excessive amounts of lactic acid. The fact that most cancers have poor vascular systems has led cancer scientists to assume that such cells are deprived of a normal supply of oxygen. Researchers believe that without sufficient oxygen, cancer cells must revert to fermentation for their energy supply and this is what causes them to produce excessive lactic acid. I challenge this traditional assumption and suggest instead that cancer cells have dysfunctional mitochondria, which prevents their use of the citric acid [Krebs] cycle. Consequently, pyruvic acid, the end product of glycolysis, which normally would enter the mitochondria for its total combustion into energy, is instead converted to lactic acid. Evidence exists to support this hypothesis which, when acknowledged, could dynamically impact both cancer research and the treatment of all forms of cancer.

Hypothesis

It is reported that cancer cells can produce 40 times more lactic acid than normal cells.1 Many primitive life forms cannot survive in an oxygen environment and therefore derive their energy from fermentation. In this process they normally produce inordinate amounts of lactic acid. Cancer scientists have assumed that since cancer cells usually have poor vascular systems, they lack oxygen and therefore revert to fermentation or anaerobic metabolism for their major source of energy. Researchers believe it is the lack of oxygen that causes cancer cells to produce excessive lactic acid.

The Dysfunctional Mitochondria Hypothesis

I believe that strong scientific evidence supports my hypothesis that dysfunctional mitochondria—not oxygen insufficiency—cause the large quantities of lactic acid produced by cancer cells. The confirmation of this hypothesis would drastically impact future treatment of all forms of cancer.

Evidence for the Hypothesis

Predominance of glycolysis and [the] Cori cycle, instead of [the] Krebs or citric acid cycle, in cancer cells.

In 1956 Warburg2 reported that all cancer cells have defective mitochondria, and they all produce excessive lactic acid. But he believed then—as the general cancer community continues to believe— that cancer cells produce this lactic acid because they do not receive sufficient oxygen. I propose that there is strong scientific evidence to indicate that injury to their mitochondria, causes cancer cells to break down glucose into lactic acid and then glycogen instead of carbon dioxide and water. This forces cancer cells to depend almost exclusively upon glycolysis as their major source of energy.

Most cancers evolve from epithelial cells and the remainder from connective tissues, nerve, and muscle. Unlike muscle cells, normal epithelial cells produce only minimal amounts of lactic acid. Cancerous epithelial cells, however, are characterized by their production of excessive lactic acid.

Normal epithelial cells derive approximately 20 percent of their daily energy needs from glycolysis and perhaps as much as 70 percent from the Krebs, or citric acid, cycle of metabolism.3 In glycolysis, glucose is broken down into pyruvic acid, which is then carried into the mitochondria and totally converted into carbon dioxide and water by the Krebs cycle. Fatty acids and waste products of amino acids are also converted into energy by the enzymes in this citric acid cycle.

As already mentioned, cancer cells that cannot utilize the Krebs cycle have difficulty meeting their daily energy needs because they must depend almost exclusively upon glycolysis for their daily energy.

I propose that cancer cells cannot utilize the Krebs cycle as efficiently as normal cells, if at all. Consequently they must convert pyruvic acid into lactic acid and must also increase the production and activities of their glycolytic enzymes in order to survive. The lactic acid so produced can then serve as a source of fuel by being carried to the liver, reconverted into glucose via the pathway of glycogen (Cori cycle), and finally returned to the cancer cells.

To support this hypothesis, I cite the following studies. Oberley and several other investigators have reported that cancer cells have little or no superoxide dismutase (SD) in their mitochondria.4,5,6,7,8 Without adequate protection from SD, superoxide—a normal, toxic free-radical byproduct of the Krebs cycle of metabolism—would injure the genes or proteins in the mitochondria. This would impair the function of the Krebs cycle and prevent the entry of pyruvic acid into the mitochondria. Consequently, once the mitochondria are injured, pyruvic acid must be converted into lactic acid instead of its normal breakdown into carbon dioxide and water.

Over the past years, various scientists working in AIDS research have reported that drugs used in the treatment of patients with HIV injure the DNA of their mitochondria.9,10,11,12 This alters the cells' oxidoreduction status and causes a functional impairment of the Krebs cycle. Consequently, the pyruvic acid resulting from glycolysis cannot be carried into the mitochondria for total combustion into energy and is instead converted into lactic acid. This, I propose, is the same reason that cancer cells produce excessive lactic acid: they have dysfunctional mitochondria and not because they are deprived of adequate oxygen. (See Diagram)


Key: OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane; LDH, lactate dehydrogenase; PDHc, pyruvate dehydrogenase complex FADH2, reduced form of flavin adenine dinucleotide; ANT, adenine nucleotide translocator. Source: AIDS, 1998;12 (14): 1738.

Figure: Schematic Presentation of Pyruvate Oxidation Pathway Leading to ATP Production

When oxidative phosphorylation function is interrupted, ATP production will decline and the NADH/NAD+ ratio will rise, followed by 1) impairment of the flux through the Krebs cycle, 2) channeling of acetyl-coenzyme A (CoA) towards ketogenesis, 3) lactic acidemia, and 4) an increased lactate-to-pyruvate ratio.

Burk and Kidd provide further evidence that cancer cells have defective mitochondria. When they added succinate[*] to various cancer cell lines, there was little or no increase in respiration, in contrast to the considerable increases obtained with virtually all normal tissues.13Succinate is a normal intermediate substrate of the Krebs cycle metabolism.

[*This note does not appear in the original text. As defined in Merriam-Webster online, succinate is a salt or ester of succinic acid, a crystalline dicarboxylic acid, C4H6O4, found widely in nature and active in energy-yielding metabolic reactions.]

It is also known that cancer cells have a several-fold increase in glycolytic enzymes, compared with normal cells14, indicating the overall increased demand placed upon glycolysis to meet daily energy needs.

Numerous studies, including the work or Chi Van Dang15 and Quillin16, show that cancer cells are such incredible consumers of sugar that they will self-destruct when deprived of glucose.

Further evidence that cancer cells depend almost exclusive[ly] upon glucose and glycolysis for their major supply of energy can be demonstrated through the use of the PET [positron emission tomography] scan—regarded as one of the ultimate cancer-detection tools. Through the use of radioactive glucose, the PET scan can detect cancer cells by the amount of glucose they consume.

Conclusion

I present a hypothesis and evidence to support my contention that cancer cells produce excessive lactic acid, not because of oxygen insufficiency, but because of their dysfunctional mitochondria. This causes them to rely almost exclusively upon glucose as their major source of energy. Confirmation of this hypothesis will dramatically affect the development of future treatments for cancer. If cancer cells must depend almost entirely upon glycolysis for their major source of energy, any drug or protocol that can destroy or cripple glycolysis would prove efficacious in treating all cancers because glycolysis and the Krebs cycle function similarly in all cells. Finding that unique characteristic of cancer cells—common to all cancers, but distinguishable from healthy body cell— is the "holy Grail" of cancer research.

It is well established that caloric restriction in the daily diet reduces tumor size in laboratory animals. Kritchevsky's studies with rats show that just a 10-percent caloric restriction reduced tumor size and that a 40-percent caloric restriction caused tumors to disappear completely.17 I contend one reason that caloric restriction results in tumor shrinkage is that it contributes to the increase of ketones in the blood. This in turn inhibits the activity of phosphofructokinase, an enzyme that plays a key role in the regulation of glycolysis.

We learn in our textbooks that ketones can inhibit the functions of phosphofructokinase.18 On a restricted caloric intake, especially one reduced by 40 percent, the body must burn its own fat as a source of fuel. Fats are converted into ketones by the liver and then deposited into the blood for distribution to cells throughout the body. Normal cells can burn fats and ketones in their Krebs cycle and can survive without glycolysis. Cancer cells, however, would have difficulty surviving without a functional phosphofructokinase in glycolysis. While a 40-percent reduction in calories may not be practical to reduce tumor size in humans, the same benefits may be realized with a low-carbohydrate, ketogenic diet.

Citric acid, an intermediary product of the Krebs cycle metabolism, has also been reported to block the actions of phosphofructokinase.19 A low-carbohydrate, high-fat diet to increase the blood levels of ketones, along with supplements or foods rich in citric acid, can impair glycolysis and may prove a beneficial adjunct to chemotherapy in the treatment of many cancers. With confirmation of this hypothesis, testing tumors for lactic acid production will prove a useful tool in designing dietary and nutritional protocols for complementing chemotherapy or conventional medicine in the treatment of cancer. Protocols that include well-designed dietary and nutritional programs, along with drugs that target the enzymes that function in glycolysis, warrant serious consideration in the treatment of most forms of advanced cancers.



References

  1. H. Holm, E. Staedt, G. Schlickeiser, H.J. Gunther, and H. Leweling, "Substrate Balances across Colonic Carcinomas in Humans," Cancer Research 55 (1995):1373–78.
  2. O. Warburg, "On the Origin of Cancer Cells," Science 23 (1956):309–14.
  3. H.A. Harper, V.W. Rodwell, and P.A. Mayes, "Metabolism of Carbohydrates," in Review of Physiological Chemistry (Los Altos, CA: Lange Medical Publications, 1979), 294.
  4. D.K. St. Clair and L.W. Oberley, "Manganese Superoxide Dismutase Expression in Human Cancer Cells: A Possible Role of mRNA Processing," Free Radical Research Communications 12 and 13 Pt. 2 (1991): 771–78.
  5. L.W. Oberley, T.D. Oberley, and G.R. Buettner, "Cell Differentiation, Aging, and Cancer: The Possible Roles of Superoxide and Superoxide Dismutases," Medical Hypotheses 6(3) (1980): 249–68.
  6. ———, "Cell Division in Normal and Transformed Cells: the Possible Role of Superoxide and Hydrogen Peroxide," Medical Hypotheses 7 (1) 1981: 21–42.
  7. L.W. Oberley and G.R. Buettner, "Role of Superoxide Dismutase in Cancer: a Review," Cancer Research 39 (4) (1979): 1141–49.
  8. S. Borrello, M.E. De Leo, and T. Galeotti, "Defective Gene Expression of MnSOD in Cancer Cells," Molecular Aspects of Medicine 14 (3) 1993: 253–38.
  9. K. Brinkman, J.M. Hadewych, T. Hofstede, D.M. Burger, J.A. Smeitink, and P.P. Koopmans, "Adverse Effects of Reverse Transcriptase Inhibitors: Mitocochondrial Toxicity as Common Pathway," AIDS 12 (1998): 1735–44.
  10. W. Lewis and F.W. Perrino, "Severe Toxicity of Fialuridine (FIAU)," New England Journal of Medicine 334 (1996): 1136–38.
  11. M.N. Swartz, "Mitochondrial Toxicity: New Adverse Drug Effects," New England Journal of Medicine 333 (1995): 1146–48.
  12. R. McKenzie, M.W. Fried, R. Sallie, et al., "Hepatic Failure and Nucleoside Analogue for Chronic Hepatitis B," New England Journal of Medicine 333 (1995): 1099–1105.
  13. D. Burk, Symposium on Respiratory Enzymes (Madison, WI: University of Wisconsin Press, 1942), 235. Also reported in J.G. Kidd, R.J. Winzler, and D. Burk, "Comparative Glycolytic and Respiratory Metabolism of Homologous Normal, Benign, and Malignant Rabbit Tissues," Cancer Research 4 (1944): 547.
  14. A.L. Schade, "Enzymic Studies on Ascitic Tumors and their Host's Blood Plasmas," Biochimica et Biophysica Acta12 (1953): 163–71.
  15. C.V. Dang, "Unique Glucose Dependent Apoptotic Pathway Induced by CMYC," Proceedings of the National Academy of Sciences 95 (1998): 1511–16.
  16. P. Quillin, "Cancer's Sweet Tooth," Nutrition Science News April 2000, 1–8.
  17. D. Kritchevsky, Journal of the National Cancer Institute 90 (1998): 1766.
  18. H.A. Harper, V.W. Rodwell, P.A. Mayes, "Metabolism of Carbohydrates and Lipid Metabolism," in Review of Practical Physiological Chemistry (Los Altos, CA: Lange Medical Publications, 1979), 370.
  19. Ibid., "Regulation of Carbohydrate and Lipid Metabolism," 371.
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