title: Survivin inhibition is critical for Bcl-2 inhibitor-induced apoptosis in hepatocellular carcinoma cells.
abstract: Our study aims to study the therapeutic effects of a novel Bcl-2 inhibitor, ABT-263, on hepatocellular carcinoma (HCC) and to provide primary preclinical data for future clinical trial with ABT-263. In this study we showed that Bcl-xL and survivin were up-regulated in HCC cell lines and human liver cancer tissues. Clinic used ABT-263 single treatment had no apoptotic effects on HCC cells whereas higher doses of ABT-263 did. Interestingly, the combination treatment of ABT-263 with survivin inhibitor YM-155 could result in significant apoptosis in HCC cells. Survivin inhibition through gene silencing significantly enhanced ABT-263 to induce apoptosis in HCC cells. We found that low dose of ABT-263 single treatment resulted in ERK activation and survivin up-regulation, which might be involved in the resistance of HCC cells to ABT-263 since blockade of ERK activation sensitized ABT-263-induced apoptosis. Importantly, ABT-263 and YM-155 combination treatment had no apoptotic effects on normal human hepatocytes. Taken together, these data suggest the combination treatment of Bcl-2 inhibitor and survivin inhibition may have a great potential for liver cancer therapy.
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Xiangxuan
authors.initials: X
authors.lastname: Zhao
authors.forename: Olorunseun O
authors.initials: OO
authors.lastname: Ogunwobi
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020868:Gene Silencing; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D008113:Liver Neoplasms / Q000473:pathology*; D009285:Naphthoquinones / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology; D000077022:Survivin
chemical_list: D000814:Aniline Compounds; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D000077022:Survivin; D048049:Extracellular Signal-Regulated MAP Kinases; C523798:sepantronium; C528561:navitoclax