azd2014 and Liver-Neoplasms

Topics: Animals; Carcinoma, Hepatocellular; Chromatography, High Pressure Liquid; Everolimus; Humans; Liver Neoplasms; MTOR Inhibitors; Tandem Mass Spectrometry

Histone deacetylases (HDACs) hyper-activity in hepatocellular carcinoma (HCC) is often associated with patients' poor prognosis. Our previous study has shown that resminostat, a novel HDAC inhibitor (HDACi), activated mitochondrial permeability transition pore (mPTP)-dependent apoptosis pathway in HCC cells. Here we explored the potential resminostat resistance factor by focusing on mammalian target of rapamycin (mTOR). We showed that AZD-2014, a novel mTOR kinase inhibitor, potentiated resminostat-induced cytotoxicity and proliferation inhibition in HCC cells. Molecularly, AZD-2014 enhanced resminostat-induced mPTP apoptosis pathway activation in HCC cells. Inhibition of this apoptosis pathway, by the caspase-9 specific inhibitor Ac-LEHD-CHO, the mPTP blockers (sanglifehrin A/cyclosporine A), or by shRNA-mediated knockdown of mPTP component cyclophilin-D (Cyp-D), significantly attenuated resminostat plus AZD-2014-induced cytotoxicity and apoptosis in HCC cells. Significantly, mTOR shRNA knockdown or kinase-dead mutation (Asp-2338-Ala) also sensitized HCC cells to resminostat, causing profound cytotoxicity and apoptosis induction. Together, these results suggest that mTOR could be a primary resistance factor of resminostat. Targeted inhibition of mTOR may thus significantly sensitize HCC cells to resminostat.

Topics: Apoptosis; Benzamides; Carcinoma, Hepatocellular; Drug Synergism; Gene Silencing; Hep G2 Cells; Humans; Hydroxamic Acids; Liver Neoplasms; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Morpholines; Mutation; Pyrimidines; Sulfonamides; TOR Serine-Threonine Kinases