Metformin and Dichloroacetate Suppress Proliferation of Liver Cancer Cells by Inhibiting mTOR Complex 1 > REFERENCE LIBRARY

Abstract: The Warburg effect is important for cancer cell proliferation. This phenomenon can

be flexible by interaction between glycolysis and mitochondrial oxidation for energy production.

We aimed to investigate the anticancer effects of the pyruvate dehydrogenase kinase inhibitor,

dichloroacetate (DCA) and the mitochondrial respiratory complex I inhibitor metformin in liver

cancer cells. The anticancer effect of DCA and/or metformin on HepG2, PLC/PRF5 human liver

cancer cell lines, MH-134 murine hepatoma cell lines, and primary normal hepatocytes using MTT

assay. Inhibition of lactate/ATP production and intracellular reactive oxygen species generation by

DCA and metformin was investigated. Inhibition of PI3K/Akt/mTOR complex I was evaluated to

see whether it occurred through AMPK signaling. Anticancer effects of a combination treatment of

DCA and metformin were evaluated in HCC murine model. The results showed that metformin and

DCA effectively induced apoptosis in liver cancer cells. A combination treatment of metformin and

DCA did not affect viability of primary normal hepatocytes. Metformin upregulated glycolysis in

liver cancer cells, thereby increasing sensitivity to the DCA treatment. Metformin and DCA inhibited

mTOR complex I signaling through upregulated AMPK-independent REDD1. In addition, metformin

and DCA increased reactive oxygen species levels in liver cancer cells, which induced apoptosis. A

combination treatment of metformin and DCA significantly suppressed the tumor growth of liver

cancer cells using in vivo xenograft model. Taken together, the combined treatment of metformin

and DCA suppressed the growth of liver cancer cells. This strategy may be effective for patients with

advanced liver cancer.