I am sending an excellent article on the subject - I hope it doesn't get 
clipped for having too many lines -- if it does I can send it privately. Liz
 
   
   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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