How May Diabetes Drugs Work Against Cancer?

Scientists have identified a major mitochondrial pathway that allows cancer cells to survive in a low-glucose environment. This may explain why anticancer properties are associated with the biguanides class of diabetes drugs, which includes metformin.

A number of retrospective studies have shown that the widely used diabetes drug metformin can benefit some cancer patients. Despite this intriguing correlation, how metformin might exert its anticancer effects and, perhaps more importantly, in which patients has been unclear.

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Now, scientists at the Whitehead Institute in Cambridge, Massachusetts, are beginning to unravel this mystery. By finding cancer cells with defects in this mitochondrial pathway or with impaired glucose utilization, the scientists can predict which tumor will be sensitive to the diabetes drugs known to inhibit the pathway in question. Their work was described in Nature (2014; doi:10.1038/nature13110).

To study how cancer cells survive in the kind of low-glucose environment found within cancerous tumors, postdoctoral researchers Kıvanç Birsoy, PhD, and Richard Possemato, PhD, in the laboratory of David Sabatini, MD, PhD, developed a system that circulates low-nutrient media continuously around cells. Of the 30 cancer cell lines tested within this system, most appeared unaffected by a lack of glucose. However, a few of the lines thrived and reproduced rapidly, while others struggled. The varied responses to a glucose shortage were puzzling.

"No one really understood why cancer cells had these responses or whether they were important for the formation of the tumor," said Possemato. "The cancer relevance of the alterations that we found as underlying this response to low glucose will still need to be investigated."

The scientists wondered whether certain cancer cells' susceptibility to a low glucose environment could be exploited to attack tumors. They screened overly distressed cells for genes whose suppression improved or further hindered the cells' survival rates. The screen flagged genes involved in glucose transportation and oxidative phosphorylation, a metabolic pathway in mitochondria. The powerhouses of a cell, mitochondria are membrane-bound organelles with their own DNA, including genes that control oxidative phosphorylation.

The scientists hypothesized impairing mitochondrial function with biguanides could push mitochondria beyond their limits, which would negatively affect cancer cells. They tested their hypothesis in cell lines with defects in glucose utilization and with mitochondrial DNA mutations, and found that these cells had higher sensitivity than control cells to phenformin. Phenformin is a more potent biguanide than metformin.

They then tested phenformin's effectiveness in mice implanted with tumors derived from low-glucose-sensitive cancer cells. The drug inhibited the tumors' growth.

"These results show that mitochondrial DNA mutations and glucose import defects can be used as biomarkers for biguanide sensitivity to determine if a cancer patient might benefit from these drugs," said Birsoy. "And this is the first time that anyone has shown that the direct cytotoxic effects of this class of drugs, including metformin and phenformin, on cancer cells are mediated through their effect on mitochondria."

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