Doctor A.P. John

Abstract: Hypothesis

This scientific article by cancer scientist Angelo John appears in the October 2001 issue (Volume 57, Number 4) pages 429-431 of the prestigious journal Medical Hypotheses.

Dysfunctional mitochondria, not oxygen insufficiency, cause cancer cells to produce inordinate amounts of lactic acid. The impact of this on the treatment of cancer.

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 prevent their use of the citric acid cycle. Consequently, pyruvic acid, the normal 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.

It is reported that cancer cells can produce forty times more lactic acid than normal cells. (l) 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 for their major source of energy. Researchers believe it is the lack of oxygen that causes cancer cells to produce excessive lactic acid.

Evidence for the Hypothesis

Predominance of Cori cycle, instead of Krebs cycle, in cancer cells.

In 1956 Warburg (2) 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 mitochondrias, cause 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. However, cancerous epithelial cells, are characterized by their production of excessive lactic acid.

Normal epithelial cells derive approximately twenty percent of their daily energy needs from glycolysis and perhaps as much as seventy 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, re-converted 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, 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. Not because they are deprived of adequate oxygen. (See figure 1.)

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. (13) Succinate is a normal intermediate substrate of the Krebs cycle metabolism.

Finally, cancer cells are also known to have an increase in glycolytic enzymes, compared with normal cells, (l4) indicating the overall increased demand placed upon glycolysis to meet daily energy needs.

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. 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 cells, is the "holy Grail" of cancer research.

It has been well established that caloric restriction in the daily diet reduces tumor size in laboratory animals. Kritchevsky's studies with rats show that just a ten percent caloric restriction reduced tumor size and that a forty percent caloric restriction caused tumors to disappear completely. (l5) 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. (l6) On a restricted caloric intake, especially one reduced by 40%, 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 forty 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. (l7) A low carbohydrate, high fat diet to increase the blood levels of ketones, along with supplements or foods rich in citric acid may some day 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.

Figure 1.

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 i impairment of the flux through the Krebs cycle, ii channeling of acetyl-coenzyme A (CoA) towards ketogenesis, iii lactic acidaemia, and iv an increased lactate/pyruvate ratio.

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)

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institute for cancer research

A.P.John