Inhibition of Bcl-2 improves effect of LCL161, a SMAC mimetic, in hepatocellular carcinoma cells

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• 作者：Kuen-Feng Chen^a ; ^b ; ¹ ; ^{kfchen1970@ntu.edu.tw} ; Jing-Ping Lin^a ; ^b ; ¹ ; ^{flower827@gmail.com} ; Chung-Wai Shiau^d ; ¹ ; ^{cwshiau@ym.edu.tw} ; Wei-Tien Tai^a ; ^b ; ^{aces0125@hotmail.com} ; Chun-Yu Liu^d ; ^e ; ^{liuchunyu_tw@yahoo.com.tw} ; Hui-Chuan Yu^a ; ^b ; ^{gane-mai@yahoo.com.tw} ; Pei-Jer Chen^a ; ^{peijerchen@ntu.edu.tw} ; Ann-Lii Cheng^b ; ^c ; ^{alcheng@ntu.edu.tw}
• 关键词：HCC ; hepatocellular carcinoma ; IAP ; inhibitor of apoptosis ; SMAC ; second mitochondrial activator of caspases ; TRAIL ; tumor necrosis factor-related apoptosis-inducing ligand ; PARP ; polypolymerase ; DMEM ; Dulbecco's modified Eagle's medium ; FBS ; fetal bovine
• 刊名：Biochemical Pharmacology
• 出版年：2012
• 期刊代码：2_00062952
• 类别：pha
• 出版时间：1 August, 2012
• 卷：84
• 期：3
• 页码：268-277
• 文件大小：1380 K

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.