ANTICANCER MECHANISM OF METFORMIN

The drug metformin, which is approved for the treatment of type 2 diabetes, has been tested in clinical trials as a tumor suppressor in different cancers due to its role in activating the AMPK signaling pathway. However, a new study by Liu et al published in Proceedings of the National Academy of Science suggests that metformin may suppress tumor cell proliferation in glioblastoma through an AMPK-independent mechanism and that activation of the AMPK pathway may instead fuel malignant cell proliferation.

To test whether activation of AMPK stops or fosters tumor growth, scientists fromCincinnati Children’s Hospital Medical Center and other institutions conducted laboratory tests on human and mouse glioblastoma cells to determine metformin’s anticancer properties. When the researchers compared normal human and mouse tissue with the glioblastoma cells, they found that AMPK was highly active in the glioblastoma cells, suggesting that the way metformin reduces cancer growth may not involve AMPK.

Study Findings

The investigators then treated the human glioblastoma cells with metformin and conducted a series of genetic tests to determine the molecular pathways it uses to stop cancer growth. They found that the drug blocked tumor growth by directly inhibiting the mTOR pathway through promotion of an interaction between two upstream molecules that stop the pathway’s function.

To further test their findings that AMPK activation by metformin is not involved in stopping cancer growth, the researchers then treated the glioblastoma cells with A769662, a compound that directly binds to AMPK. Treatment with A769662 did not kill glioblastoma cells, further suggesting that AMPK activation is not involved in stopping tumor growth.

Interpret Clinical Trial Results With Caution

“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,” Biplab Dasgupta, PhD, principal investigator of the study and a researcher in the Division of Hematology/Oncology at Cincinnati Children’s Hospital Medical Center, said in a statement. “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.”

Dr. Dasgupta and his colleagues are currently testing direct genetic inhibition of AMPK to determine how it impacts human glioblastoma cells. Although the research is not completed, preliminary results suggest that blocking AMPK activity appears to kill a significant number of the glioblastoma cells.

The study was funded by CancerFreeKids, the Smith-Brinker Golf Foundation, a Cincinnati Children’s Trustee Scholar Grant, and the National Institutes of Health. The study authors reported no conflict of interest.