Survivin inhibition is critical for Bcl-2 inhibitor-induced apoptosis in hepatocellular carcinoma cells

• Published in: PloS one Vol. 6; no. 8; p. e21980
• Main Authors: Zhao, Xiangxuan, Ogunwobi, Olorunseun O, Liu, Chen
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.08.2011; Public Library of Science (PLoS)
• Subjects: Activation; Aniline Compounds - pharmacology; Apoptosis; Apoptosis - drug effects; Bcl-2 protein; Bcl-x protein; Biology; Cancer; Cancer therapies; Carcinoma, Hepatocellular - pathology; Cell growth; Cell Line, Tumor; Cytochrome; Drug therapy; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Silencing; Genetic engineering; Health aspects; Hepatocellular carcinoma; Hepatocytes; Hepatocytes - drug effects; Humans; Imidazoles - pharmacology; Immunoglobulins; Immunology; Inhibition; Inhibitor of Apoptosis Proteins - antagonists & inhibitors; Inhibitor of Apoptosis Proteins - genetics; Inhibitors; Laboratories; Liver; Liver cancer; Liver cirrhosis; Liver Neoplasms - pathology; Lung cancer; Medical research; Medicine; Naphthoquinones - pharmacology; Pathology; Proteins; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Sulfonamides - pharmacology; Survivin; Tissues; Tumor cell lines; Tumors; Florida; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0021980

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.