The diabetes drug metformin is undergoing investigation as a potential treatment for different cancers in numerous clinical trials. Several of the studies point to its apparent activation of adenosine monophosphate-activated protein kinase (AMPK), a molecular regulator of cell metabolism, to suppress tumor growth.

But new research appearing in Proceedings of the National Academy of Sciences (PNAS 2014; doi:10.1073/pnas.1311121111) suggests that activation of AMPK may actually fuel cancer growth. Researchers from Cincinnati Children’s Hospital Medical Center in Ohio who led the study also recommend that clinicians testing metformin as a cancer treatment consider a careful reevaluation of their clinical data.

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

In the body, metformin suppresses the actions of insulin and insulin-like growth factors—two molecules that support cancer growth—and also likely independent of AMPK, according to principal investigator Biplab Dasgupta, PhD.

“Our findings do not suggest that clinical trials using metformin should be stopped. Metformin appears to be a very useful drug, but the drug’s mechanism of cancer suppression is not clear,” Dasgupta said. “However, our findings unveil a potential role for AMPK as a tumor growth supporter, not a suppressor, in the type of cancer that we study. This is why clinicians using metformin in clinical trials should use caution during data interpretation.”

Dasgupta and his research colleagues decided to tackle the question of metformin’s anticancer properties because some studies point to AMPK as a tumor suppressor, whereas others have suggested it can promote tumor growth. Ultimately, an accurate understanding of AMPK’s role—and how a drug like metformin does stop cancer—will likely be important to continued improvement of targeted cancer therapies, he said.

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 genetic tests to determine that metformin directly inhibited the mTOR pathway (and the cancer) by promoting the interaction of two upstream molecules that stop the pathway’s function.

To further verify that AMPK activation by metformin is not involved in stopping the growth of cancer, the researchers also treated the glioblastoma cells with a more specific AMPK-activating compound, A769662, which directly binds to AMPK. They found that the treatment did not kill glioblastoma cells.

Dasgupta and his colleagues are continuing their research by testing direct genetic inhibition of AMPK to see how it impacts human glioblastoma cells. Although that research still has to be completed and the results verified, he said that preliminary indications suggest blocking AMPK appears to kill a significant number of the glioblastoma cells.