https://scholars.lib.ntu.edu.tw/handle/123456789/568489
標題: | Inhibition of Bcl-2 improves effect of LCL161, a SMAC mimetic, in hepatocellular carcinoma cells | 作者: | Chen K.-F. Lin J.-P. Shiau C.-W. Tai W.-T. Liu C.-Y. Yu H.-C. PEI-JER CHEN ANN-LII CHENG |
公開日期: | 2012 | 出版社: | Elsevier Inc. | 卷: | 84 | 期: | 3 | 起(迄)頁: | 268-277 | 來源出版物: | Biochemical Pharmacology | 摘要: | In this study, we investigated the effect of LCL161, a SMAC mimetic, in hepatocellular carcinoma (HCC). LCL161 showed differential effects on apoptosis in four HCC cell lines, and the endogenous level of Bcl-2 determined the sensitivity of HCC cells to LCL161. Cytotoxicity and apoptosis were observed in sensitive PLC5 and Hep3B cells that express lower levels of Bcl-2, but not in resistant Huh-7 and SK-Hep1 cells with higher Bcl-2 expression. Down regulation of Bcl-2 by small interference RNA overcame the resistance to LCL161 in Huh-7, and the apoptotic effect was rescued in Bcl-2-expressing Hep3B. To test the hypothesis that Bcl-2 determines the sensitivity of HCC cells to LCL161, we assayed the biological effect of SC-2001, a novel Bcl-2 inhibitor derived from obatoclax, in LCL161-resistant cell lines. Huh-7 cells co-treated with LCL161 and SC-2001 showed a significant dose-dependent apoptotic effect demonstrated by sub-G1 assay and cleavage of PARP. Furthermore, the combination index (CI) of LCL161 and SC-2001 showed a convincing synergism in resistant Huh-7. In addition, the combinational therapy showed significant growth inhibition in Huh-7-bearing xenograft tumors. Notably, down regulation of Bcl-2 was observed in a tumor sample treated with LCL161 and SC-2001. In conclusion, targeting Bcl-2 with SC-2001 overcomes drug resistance to LCL161 in HCC cells thus suggesting a new anti-IAP combinational therapy for HCC. ? 2012 Elsevier Inc. All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84984558764&doi=10.1016%2fj.bcp.2012.04.023&partnerID=40&md5=9e65d3106ed3da5df527bc38bd062609 https://scholars.lib.ntu.edu.tw/handle/123456789/568489 |
ISSN: | 0006-2952 | DOI: | 10.1016/j.bcp.2012.04.023 | SDG/關鍵字: | antineoplastic agent; lcl 161; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; obatoclax; protein bcl 2; RNA; sc 2001; second mitochondrial activator of caspase; unclassified drug; animal experiment; animal model; apoptosis; article; cancer cell; cancer resistance; controlled study; cytotoxicity; down regulation; drug mechanism; drug potentiation; human; human cell; in vivo study; male; mouse; nonhuman; priority journal; protein cleavage; protein expression; RNA interference |
顯示於: | 臨床醫學研究所 |
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