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Drug allows cancer suicide
18 JANUARY 2007

Promoting cancer suicide?
A model of a molecule, looks like globes held together by sticks For more than 70 years, scientists have known that cancer affects mitochondria, the tiny structures that process energy inside cells. Mitochondria normally get their power from oxidizing the sugar glucose, but in tumors, the mitochondria quit functioning, and tumor cells resort to breaking down glucose without oxygen.

Dichloroacetate (DCA) is a simple molecule with two oxygens, two chlorines, and two carbons. DCA has been used to treat a rare illness in mitochondria, which process energy inside cells. Unlike many new cancer drugs, you can take DCA by mouth. Courtesy University of Alberta

Although most scientists thought mitochondrial malfunction was a result, not a cause, of cancer, it now seems that it could be integral to the disease process.

This matters for two reasons. First, mitochondria are critical triggers of a cancer-killing mechanism called programmed cell death, AKA apoptosis or cellular suicide. In a healthy body, tumor cells should commit suicide, not grow.

And second, the new understanding could reveal new targets for cancer drugs.

Managing mitochondrial malfunction
These implications are the background for a new study from the University of Alberta, showing that the cancer-induced decline in mitochondria can be reversed. Writing in Cancer Cell, associate professor of medicine Evangelos Michelakis and colleagues describe experiments performed on human cancer cells -- in lab dishes and in experimental animals.

Researcher: The drug 'DCA can be selective for cancer because it attacks a fundamental process in cancer development that is unique to cancer cells.'Under normal conditions, mitochondria "burn" -- oxidize -- glucose to make usable energy for the cell. When oxygen is absent, cells resort to glycolysis, a breakdown process that liberates lactic acid. Lactic acid helps cause muscle cramping during exercise, but it can also help cancer cells move in the body -- to metastasize.

Scientists have long known that mitochondria play a role in cancer, says Michelakis. When the mitochondria quit producing energy, cells cope by breaking down glucose outside the mitochondria. Because this process is inefficient, it needs abnormal amounts of glucose, which happens to be why cancer cells can be detected with PET scans. Positron emission tomography measures glucose usage, Michelakis says. "PET detects cancer because tumors have shut off the mitochondria, and have to rely on less efficient means of generating energy. The cancer cells are drinking glucose like crazy, and this distinguishes them from normal cells."

As evidence mounted for a major role of mitochondria in cancer, Michelakis, a specialist in cardiology who specializes in energy metabolism inside cells, Sebastian Bonnet and their colleagues began to wonder if they could restore the mitochondria and thereby affect cancer. They focused on dichloroacetate (DCA), a drug that pushes glucose metabolism back toward normal oxidation, and is sometimes used to treat mitochondrial problems.

Computer image of large tumor on right hand side of body, shrinking over time
After three weeks, the tumor is much smaller in the DCA-treated rat than in the control rat -- showing either shrinkage or slower growth. Courtesy University of Alberta

Cancer: shrink thyself!
When the researchers injected human lung cancer cells into rats, tumors shrank significantly in animals that got DCA, compared to the animals that did not get the drug. Tests showed that apoptosis was operating in the tumors in these DCA-treated animals, but not in the control animals.graph with varying degrees of incline

The drug DCA reduces tumors but does not eliminate them. Green: DCA was given when the rats are injected with tumor cells. Red: DCA was given two weeks after tumor injection. Blue: Control animals got tumor cells, but not DCA. Data from Bonnet et al (see below).

DCA affected tumors when it was given either before or after the cancer cells were injected, indicating that it may have a role in preventing and curing cancer.

Biochemical tests showed that mitochondria in the DCA-treated cancer cells were releasing compounds that stimulate apoptosis -- cellular suicide. Many cancer drugs work through apoptosis, but cancer cells often resist committing suicide, at least partly because the shut-down mitochondria cannot start the suicide processes. The results support a relatively new line of studies showing that mitochondria play a major role in regulating apoptosis.

While this treatment has not been tested in people or any animal except rats, DCA has a number of theoretical advantages over expensive, highly toxic cancer treatments: It is not patented, and therefore cheap. It is a small molecule that can be taken orally. And more than 30 years of medical use has revealed minimal side effects.

Programmed cell death with DCA
Two sharply sloping graph
DCA-treated rats had smaller tumors due to an increase in programmed cell death, as measured by TUNEL (don't even ask what that stands for!) and a decrease in proliferation, which is part of metastasis. Data from Bonnet et al (see below).

Perhaps the most intriguing aspect of the discovery is this: Damage to mitochondria is widespread in many types of cancer, Michelakis says, indicating that DCA could have broad use -- if it works as well in people as in rats. The next step, he adds, is to start a small trial among patients with the three cancers already tested (glioblastoma, green-tinted photo of cancer cella type of brain cancer; non-small-cell lung cancer; and breast cancer). The details of upcoming trials "will depend on funding," he adds. Because DCA, cannot be patented, "industry is not particularly interested" in funding research.

But because DCA is already on the market, the first trial could begin in a few months.

Breast cancer cell. Photo: NIH, courtesy National Cancer Institute.

At this point, Michelakis is enthusiastic that energy metabolism may point to ways to overcome cancer. "DCA attacks a fundamental and unique property of cancer. It puts the mitochondria back in the normal condition, and because the mitochondria can control cell death, that also comes back into the picture."

One possible therapeutic approach, he says, would use DCA to sensitize tumor cells to apoptosis, and then attack the cancer with standard chemotherapy drugs. Ideally, lower doses of the highly toxic chemotherapy drugs would be effective once tumor cells lose their immunity to programmed cell death.

— David Tenenbaum

• Bonnet et al., A Mitochondria-K+ Channel Axis Is Suppressed in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth, Cancer Cell (2007), doi:10.1016/j.ccr.2006.10.020

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