The diabetes treatment metformin could be combined with a therapy that inhibits thet MDM2 protein to suppress the growth of malignant mesothelioma cells, a study reports.
Researchers said the findings have shed light on the mechanisms underlying the disease, and could lead to new approaches to treating it.
Both metformin and the MDM2 inhibitor nutlin-3a can inhibit cancer pathways. Metformin has yet to be used in cancer therapy, however. It treats type 2 diabetes, the most common type, which affects 27 million Americans.
Metformin inhibits the activation of mTOR pathway. Nutlin-3a inhibits the MDM2 cell destruction pathway.
Cancer cells use different pathways than normal cells to survive and proliferate. Which pathways are activated and which mechanisms underlie the activation are different, depending on the type of cancer.
The mTOR pathway is activated in a lot of cancers, research has indicated. The mTOR inhibitor Afinitor (everolimus) suppresses the growth of kidney and breast cancers by blocking the pathway.
Metformin is another mTOR inhibitor that studies have suggested could fight cancer. While scientists found genetic alterations that led to the activation of mTOR in half of mesothelioma patients, metformin had yet to be examined as a treatment for the disease.
Another mechanism that helps cancer cells survive and proliferate is deactivation of a protein called p53. Under normal conditions it keeps cell proliferation under control by disposing of cells that need to be eliminated. A previous study demonstrated that inhibiting the FAK and MDM2 proteins can counteract the advantages that cancer cells obtain when p53 is shut down.
With both mTOR and MDM2-p53 inhibitors exhibiting cancer-fighting properties, researchers decided to try both to treat mesothelioma cells grown in a lab.
Metformin was the mTOR inhibitor they chose, and nutlin-3a, an experimental therapy, the MDM2 inhibitor. Using metformin or nutlin-3a by themselves to treat several mesothelioma cells reduced proliferation and increased cell death. But when the inhibitors were used together, the anti-cancer effects were even more pronounced, researchers said.
The pathways the drugs inhibited depended on which experimental cell line was tested. Despite the genetic and molecular variations that mesothelioma can present, the researchers concluded, inhibiting mTOR and MDM2-p53 at the same time could be a good way to target cancer cells and bolster chemotherapy regimens.
“The present study suggests that a combinatory use of an inhibitor for mTOR and a p53-activating agent targets mesothelioma with characteristic genetic alterations and is a new therapeutic regimen,” the team wrote. “Metformin is now clinically in use and some of the MDM2-p53 inhibitors are under clinical trials, which indicates feasibility of the combination in mesothelioma treatments.”