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Study Questions Anticancer Mechanisms of Metformin

Drug targets mTOR pathway, not AMPK (January 13)

The diabetes drug metformin is being tested in numerous clinical trials for treating different cancers, and several studies point to its apparent activation of a molecular regulator of cell metabolism called AMPK to suppress tumor growth.

But new research published in the Proceedings of the National Academy of Sciences suggests that activation of AMPK may actually fuel cancer growth. Researchers at Cincinnati Children’s Hospital Medical Center, who led the study, also recommend that clinicians testing metformin for cancer treatment consider re-evaluating their clinical data.

The researchers report on extensive laboratory tests, which showed that metformin does stop cancer, but not by activating AMPK. Instead, in tests involving glioma brain-cancer cells, the authors found that metformin inhibits a different molecule, the mammalian target of rapamycin (mTOR), which has been linked to many other cancers.

To determine how AMPK and metformin react in the context of cancer, the researchers conducted tests using glioblastoma, a highly lethal brain cancer with no cure. Their experiments involved laboratory cultures of human glioblastoma cells and glioblastoma tumors transplanted in mice to obtain results in a living organism.

Compared with normal human and mouse tissue, the researchers found that AMPK was highly active in human and mouse glioblastoma cells. This led them to question whether the anticancer properties of metformin were independent of AMPK, and instead directed to other molecular pathways.

The researchers then treated human glioblastoma cells with metformin and conducted a series of genetic tests to determine the molecular pathways it uses to stop cancer growth. Those tests showed that metformin directly inhibited the mTOR pathway (and the cancer) by promoting the interaction of two upstream molecules that stop the pathway’s function.

Source: CCHMC; January 13, 2014.

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