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

Biochemical Pharmacology
Kuen-Feng ChenAnn-Lii Cheng

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...Continue Reading

References

Apr 1, 1990·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·S Govindarajan
Sep 2, 1993·The New England Journal of Medicine·F PezzellaD Y Mason
Apr 1, 1993·Journal of Virology·N E CrookL K Miller
Feb 28, 1998·The EMBO Journal·L O'ConnorD C Huang
Aug 15, 1998·Trends in Cell Biology·A Kelekar, C B Thompson
Jul 15, 1999·Nature Structural Biology·M G HindsC L Day
Mar 21, 2001·Cell·J ChaiP Dataa
Jun 4, 2002·Nature Reviews. Molecular Cell Biology·Guy S Salvesen, Colin S Duckett
Mar 7, 2003·Molecular Cell·Eric N ShiozakiYigong Shi
Mar 5, 2004·Biochimica Et Biophysica Acta·Juanita C SharpeRichard J Youle
Apr 2, 2005·Nature Reviews. Molecular Cell Biology·David L Vaux, John Silke
May 28, 2005·The EMBO Journal·Matthew G AnnisDavid W Andrews
Dec 22, 2005·Protein Engineering, Design & Selection : PEDS·C MadzakC Jolivalt
Jun 1, 2006·American Journal of Physiology. Renal Physiology·Alison DziarmagaPaul Goodyer
Jun 19, 2007·Apoptosis : an International Journal on Programmed Cell Death·Allison M HunterRobert G Korneluk
Jan 19, 2008·Nature Reviews. Cancer·Anthony G Letai
May 3, 2008·Cancer Research·Christin TseSteven W Elmore
Sep 30, 2008·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Josep M Llovet, Jordi Bruix
Oct 23, 2008·The Biochemical Journal·John W BlankenshipDomagoj Vucic
Jun 13, 2009·Annals of Oncology : Official Journal of the European Society for Medical Oncology·C VerslypeC van de Velde
Jan 27, 2010·Expert Opinion on Therapeutic Patents·John A Flygare, Wayne J Fairbrother
Jun 18, 2011·Pediatric Blood & Cancer·Peter J HoughtonMalcolm A Smith
Jul 12, 2011·Pediatric Blood & Cancer·Peter J HoughtonMalcolm A Smith
May 30, 2013·Expert Opinion on Therapeutic Patents·Claudio Sette

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Citations

Oct 31, 2013·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Qin QinXinchen Sun
Jan 28, 2014·Nature Biotechnology·Shawn T BeugRobert G Korneluk
May 20, 2015·Expert Opinion on Therapeutic Patents·Alexander W HirdBin Yang
Jul 23, 2014·Neoplasia : an International Journal for Oncology Research·Jung-Chen SuChung-Wai Shiau
Oct 16, 2016·Journal of Experimental & Clinical Cancer Research : CR·Chengcheng YangSida Qin
Nov 15, 2016·Nature Medicine·Marta ChesiP Leif Bergsagel
Apr 19, 2016·Biopolymers·Ramesh ChingleWilliam D Lubell
Feb 15, 2020·Cells·Emma MorrishJohn Silke
Apr 21, 2017·Apoptosis : an International Journal on Programmed Cell Death·Rama RathoreDietrich Büsselberg
Dec 7, 2018·Journal of Cellular Biochemistry·Afshin NikkhooFarhad Jadidi-Niaragh
Nov 18, 2015·Molecular Medicine Reports·Gongsheng JinBenzhong Wang
Oct 28, 2021·Journal of Medicinal Chemistry·Parima UdompholkulMaurizio Pellecchia

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