title: Activation of mPTP-dependent mitochondrial apoptosis pathway by a novel pan HDAC inhibitor resminostat in hepatocellular carcinoma cells.
abstract: Over-expression and aberrant activation of histone deacetylases (HDACs) are often associated with poor prognosis of hepatocellular carcinoma (HCC). Here, we evaluated the potential anti-hepatocellular carcinoma (HCC) cell activity by resminostat, a novel pan HDAC inhibitor (HDACi). We demonstrated that resminostat induced potent cytotoxic and anti-proliferative activity against established HCC cell lines (HepG2, HepB3, SMMC-7721) and patient-derived primary HCC cells. Further, resminostat treatment in HCC cells activated mitochondrial permeability transition pore (mPTP)-dependent apoptosis pathway, which was evidenced by physical association of cyclophilin-D and adenine nucleotide translocator 1 (ANT-1), mitochondrial depolarization, cytochrome C release and caspase-9 activation. Intriguingly, the mPTP blockers (sanglifehrin A and cyclosporine A), shRNA knockdown of cyclophilin-D or the caspase-9 inhibitor dramatically attenuated resminostat-induced HCC cell apoptosis and cytotoxicity. Reversely, HCC cells with exogenous cyclophilin-D over-expression were hyper-sensitive to resminostat. Intriguingly, a low concentration of resminostat remarkably potentiated sorafenib-induced mitochondrial apoptosis pathway activation, leading to a profound cytotoxicity in HCC cells. The results of this preclinical study indicate that resminostat (or plus sorafenib) could be further investigated as a valuable anti-HCC strategy.
authors.affiliation: Department of Infectious Disease, Linyi People's Hospital, Linyi, China.
authors.forename: Meili
authors.initials: M
authors.lastname: Fu
authors.affiliation: Department of Radiotherapy, Linyi Tumor Hospital, Linyi, China.
authors.forename: Wenhong
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Nursing, Tengzhou Central People's Hospital, Tengzhou, China.
authors.forename: Zhengling
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Nursing, Linyi People's Hospital, No. 27 Jiefang Road, Linyi 276000, Shandong, China. Electronic address: liuhaiyanlinyi5@sina.com.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology*; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D013449:Sulfonamides; C550599:resminostat
keywords: HDAC inhibitor; Hepatocellular carcinoma (HCC); Mitochondrial apoptosis pathway; Resminostat; Sorafenib; mPTP