Giving Cancer an Energy Blackout

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In the 1920s, the German researcher Dr. Otto Warburg discovered that cancer cells rely heavily on a process known as glycolysis to produce energy.

Dr. Warburg, a Nobel Prize winner, also found that cancer cells did this even when there was sufficient oxygen available for a far more efficient, oxygen-dependent energy-production process used by many normal cells, called oxidative phosphorylation. The paradox came to be known as the "Warburg effect."

Dr. Warburg believed that this "aerobic glycolysis" was at the root of cancer development, but his theory never caught on.

Over the last decade, however, there has been a resurgence of interest in learning more about cancer cell metabolism - how cancer cells produce energy and use it to grow and divide.

Cancer cell metabolism hasn't traditionally been "considered as part of the cancer problem," says Dr. Craig Thompson, scientific director at the Abramson Family Cancer Research Institute. But the renewed interest in it, he believes, "gives us a number of new avenues to investigate to see whether it can be exploited for therapeutic benefit."

And Dr. Thompson isn't the only one. A growing cadre of researchers is now delving deep into cancer cells' energy-production machinery, with the hope of finding effective ways to short-circuit it.

Tumor cells' glucose problem

The renewed focus on energy production and Warburg's discoveries from 80 years ago is an ideal case in point.

"More and more, multiple groups are looking at the molecular mechanisms behind the Warburg effect, because it's consistently observed in tumor cells," says Dr. Peng Huang, an associate professor of molecular pathology at the University of Texas M.D. Anderson Cancer Center. "Certainly, in both cell culture and animal models, we see the cancer cells' increased dependence on glycolysis."

Both glycolysis and oxidative phosphorylation begin with the ingestion of glucose by a cell. The difference resides in how the cell transforms that raw material into energy - in the form of a complex molecule called ATP - and the efficiency with which it does it. Oxidative phosphorylation can produce as much as 18 times more ATP per molecule of glucose than glycolysis.

This inefficiency leads tumor cells that are reliant on glycolysis to take up a tremendous amount of glucose. This reliance forms the basis for the now widespread use of PET scans that involve the glucose analog FDG for the detection of a number of different cancer types.

Researchers like Drs. Huang and Thompson believe tumor cells' addiction to glycolysis might represent a bona fide Achilles heel: Disrupt glycolysis and tumor cells won't be able to produce enough energy to survive. Data from laboratory and animal model studies support this belief.

But the question remains: Why do tumor cells rely on a less efficient energy-production process when they don't have to?

"It's still a matter of debate," says Dr. Huang.

Several theories have been proposed to explain this. One suggests that genetic mutations have damaged the tumor cells' mitochondria, where oxidative phosphorylation takes place, so the cell switches to an alternative energy-production pathway. Another argues that it's an adaptation that gives the cell a survival advantage once a tumor becomes larger and oxygen - but not necessarily glucose - becomes far less abundant.

Dr. Thompson admits that it's complicated and requires more intensive study.

"We need to look more closely at issues like which signaling pathways tumor cells are using when they just want to survive for the day, or if they want to engage in growth and proliferation," he says.

Mucking up the machinery

Efforts to exploit this potential tumor cell weakness are moving ahead full steam, with glycolytic inhibitors already in human clinical trials or headed in that direction.

One company, Threshold Pharmaceuticals, has based its entire therapeutic enterprise on what they call "metabolic targeting." Two of its products are currently in clinical trials, including 2DG, a glucose analog being investigated in combination with docetaxel in a phase I trial.

Because tumor cells are so hungry for glucose - particularly those that are in hypoxic regions of a tumor and are more likely to be resistant to standard chemotherapy agents - 2DG is readily taken up by tumor cells, says the scientist who developed it, Dr. Ted Lampidis.

Once inside, explains Dr. Lampidis, a professor of cell biology at the University of Miami Sylvester Cancer Center, the agent competes with regular glucose to be synthesized into ATP. However, because of the slight difference in 2DG's makeup compared with glucose, that synthesis never happens, starving the cell of energy.

"We've made tremendous progress from developing the concept of 2DG to getting it into the clinic," he says. "I see now that there's a real possibility it's going to work."

The phase I trial is almost complete and plans are under way to launch a phase II trial.

Another agent, 3-BrPA, completely eradicated large, highly glycolytic tumors in one animal model and markedly shrank similar tumors in another model. The agent's target, explains Dr. Peter Pedersen, a professor of biological chemistry at the Johns Hopkins University School of Medicine - who along with Dr. Young Ko, is moving it through preclinical studies - is an enzyme called hexokinase that is bound to the surface of mitochondria but plays a key role in both glycolysis and oxidative phosphorylation. Dr. Ko, who discovered the agent's potent anticancer activity, calls 3-BrPA a "total energy blocker."

Most recently, they've been investigating 3-BrPA's effect on different cancer cell lines.

"Once inside [the tumor cell], it's like a Trojan horse," Dr. Pedersen explains. "You see dissipation of ATP very quickly. But if you do the same thing to a hepatocyte [an important and abundant liver cell], for example, it hardly has any effect."

A number of companies have approached Dr. Petersen's lab about taking 3-BrPA into clinical trials.

By Carmen Phillips

NOBEL PRIZE WINNER SAYS CELLULAR ADAPTATION CAUSES CANCER

According to Nobel Prize Winner Otto Warburg, a normal cell deprived of 4 nutrients causes the cell to become a cancer cell by irreversibly changing the cell into a simpler form like yeast cells, which grows out of control like yeast.

In 1931 Dr. Otto Warburg was awarded the Nobel Prize in medicine for determining the role of a group of enzymes involved in aerobic (with oxygen) respiration of healthy cells. During his research he found that when a normal body cell switches from aerobic respiration to anaerobic (without oxygen) respiration the cell becomes a form of simpler cells, called cancer, similar to yeast. Like yeast and mold, cancer grows out of control.

(Respiration is the cellular process of extracting energy from the bonds of molecules of food. Aerobic respiration is highly efficient and provides plenty of energy to sustain complex life (animals). Anaerobic respiration is much less efficient and provides only enough energy to support simple life, like fungi, yeast, many forms of bacteria.)

Warburg believed what causes a cell to switch to anaerobic respiration is a cell being starved of iron and 3 B-vitamins, and also that the change to anaerobic respiration is irreversible. To this day scientists haven’t claimed he was wrong.

In presenting the Nobel Prize to Warburg, hopes were very high, “The medical world expects great things from your experiments on cancer and other tumours and experiments which seem already to be sufficiently far advanced to be able to furnish an explanation for at least one cause of the destructive and unlimited growth of these tumours. “

Nobel Prize Presentation to Warburg
Warburg’s Nobel Lecture (.pdf)
Otto Warburg: Nobel Prize in Physiology

“The Prime Cause And Prevention Of Cancer”
In June of 1966 Warburg wrote The Prime Cause and Prevention of Cancer which included this paragraph,

“To prevent cancer it is therefore proposed first to keep the speed of the blood stream so high that the venous blood still contains sufficient oxygen; second, to keep high the concentration of hemoglobin in the blood; third, to add always to the food, even of healthy people, the active groups of the respiratory enzymes; and to increase the doses of these groups, if a precancerous state has already developed. If at the same time exogenous carcinogens are excluded rigorously, then much of the endogenous cancer may be prevented today.”

In August of the same year, Warburg revised The Prime Cause and Prevention of Cancer which includes the names of the “active groups of the respiratory enzymes” he wrote of in his orginal.

“ Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause. The prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by fermentation of sugar [anaerobic respiration].

All normal body cells meet their energy needs by respiration of oxygen, whereas cancer cells meet their energy needs in great part by fermentation. All normal body cells are thus obligate aerobes, whereas all cancer cells are partial anaerobes. From the standpoint of the physics and chemistry of life this difference between normal and cancer cells is so great that one can scarcely picture a greater difference. 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, a fermentation of glucose.

Of what use is it to know the prime cause of cancer? Here is an example. In Scandinavian countries there occurs a cancer of throat and esophagus whose precursor is the so-called Plummer-Vinson syndrome. This syndrome can be healed when one adds to the diet the active groups of respiratory enzymes, for example: iron salts, riboflavin, pantothenic acid, and nicotinamide. When one can heal the precursor of a cancer, one can prevent this cancer. According to Ernest Wynder of the Sloan-Kettering Institute for Cancer Research in New York, the time has come when one can exterminate this kind of cancer with the help of the active groups of the respiratory enzymes.

It is of interest in this connection that with the help of one of these active groups of the respiratory enzymes, namely nicotinamide, tuberculosis can be healed quite as well as with streptomycin, but without the side effects of the latter. Since the sulfonamides and antibiotics, this discovery made in 1945 is the most important event in the field of chemotherapy generally, and encourages, in association with the experiences in Scandinavia, efforts to prevent cancer by dietary addition of large amounts of the active groups of the respiratory enzymes. “

http://www.encognitive.com/node/1241

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