Metformin forces a metabolic conversion that tumor cells lacking this oncogene are unable to execute.
A commonly prescribed diabetes drug kills tumor cells in mice lacking p53, according to researchers at the University of Pennsylvania School of Medicine. More than half of all human cancers have lost the p53 gene, the scientists report.
“This is the first time you can show that tumor growth is impaired by a diabetes drug,” says senior author, Craig B. Thompson, M.D., director of the Abramson Cancer Center and chairman and professor of cancer biology and medicine.
Dr. Thompson and his team have been accumulating evidence that p53, which regulates cell division, also controls several metabolic pathways in cells. For potential cancer therapies, the group hypothesized, that means a drug that affects pathways controlled by p53 could help control p53-deficient tumors.
The diabetes drug metformin activates the metabolic enzyme AMPK (AMP activated protein kinase), which exerts changes on cellular metabolism by affecting p53 function. The Penn research team say that two observational studies have shown that diabetic patients who take metformin have a lower rate of cancer diagnosis and mortality than other diabetics.
Dr. Thompson and his colleagues decided to inject human colon cancer cells that have normal p53 function into one side of mice and colon cancer cells that lack p53 into the other side. After four days, they started treating the animals with a daily injection of either a saline control solution or with metformin, using a dose comparable to diabetic treatment in humans.
The investigators found that the p53-deficient tumors in mice treated with metformin were half the size of the p53 deficient tumors in control mice. There was no difference in the size of the p53 normal tumors between the animals treated with metformin or saline. They concluded that metformin slowed the growth of the colon cancer cells that lack a normal p53 function.
The researchers discovered that metformin instructs cells to switch metabolic pathways. Instead of using oxidative phosphorylation, the cells are forced to use stress-related ones, which typically come into play when the cell is short on oxygen, glucose, or other nutrient sources. In the absence of p53, however, the cells can’t make the switch. “Without p53, if we force cells to live on alternative substrates, they can’t do it,” explains Dr. Thompson.
The Penn team reported their findings last month in Cancer Research.
