title: Inhibition of Bcl-2 improves effect of LCL161, a SMAC mimetic, in hepatocellular carcinoma cells.
abstract: 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.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. kfchen1970@ntu.edu.tw
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Lin
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.forename: Wei-Tien
authors.initials: WT
authors.lastname: Tai
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Hui-Chuan
authors.initials: HC
authors.lastname: Yu
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D040761:Biomimetic Materials / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000737:chemistry* / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; C574246:LCL161; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; C572884:SC-2001; C532637:SMAC peptide; D013844:Thiazoles