A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

Abstract

Ovarian cancer is a common gynecological cancer that is found worldwide. Class III histone deacetylase (HDAC) inhibitors, a new class of anticancer agents, induce autophagy in various human cancer cells. The aim of the present study was to investigate the antitumor activity of MHY2245, a new synthetic SIRT inhibitor, on human ovarian cancer cells. We found that MHY2245 exhibited potent cytotoxicity to SKOV3 cells in a time- and concentration-dependent manner. The cytotoxicity of MHY2245 (IC ₅₀=0.32 µM) was higher than that of doxorubicin (DOX, IC ₅₀=1.38µM) against SKOV3 cells. MHY2245 significantly inhibited SIRT1 enzyme activity, reduced the expression of SIRT1, increased cell cycle arrest at G ₂/M phase, and induced apoptotic cell death in SKOV3 cells via expression of cytochrome c, cleaved-PARP, cleaved caspase-3, and Bax. This might be associated with blocking of the pyruvate kinase M2 (PKM2)/mTOR pathway. MHY2245 also inhibited tumor growth and reduced tumor size when SKOV3 cells were transplanted into nude mice. Our results indicate that MHY2245 exerts antitumor activity against ovarian cancer cells by blocking the PKM2/mTOR pathway. We suggest that MHY2245 is a promising anticancer agent that disrupts ovarian cancer cell metabolism.