title: Synergistic effects of IAP inhibitor LCL161 and paclitaxel on hepatocellular carcinoma cells.
abstract: Inhibitor of Apoptosis Proteins (IAPs) are key regulators of apoptosis in hepatocellular carcinoma (HCC) and their expression is negatively correlated with patient survival. LCL161 is a small molecule inhibitor of IAPs that has potent antitumour activity in a range of solid tumours. In HCC, response to LCL161 therapy has shown to be mediated by Bcl-2 expression. In this study, we aim to determine whether LCL161 has any therapeutic potential in HCC. Protein expression was determined by Western blot. Cell proliferation was determined by Cell Proliferation ELISA and BrdU colorimetric assays. Apoptosis was determined by Annexin V assay. Cell cycle analysis was performed by staining cells with propidium iodide and analysed in a FACScan. Automated Cell Counter and phase contrast microscopy were used to determine the cell viability. We have found that LCL161 targets (cIAP1, cIAP2 and XIAP) were up-regulated in HCC tumours. Both high Bcl-2 expressing HuH7 cells and low Bcl-2 expressing SNU423 cells showed strong resistance to LCL161 therapy with significant effects on both apoptosis and cell viability only evident at LCL161 concentrations of ⩾100μM. At these doses there was significant inhibition of IAP targets, however there was also significant inhibition of off-target proteins including pERK and pJNK suggesting apoptosis caused by drug toxicity. However, when used in combination with paclitaxel in HuH7 and SNU423 cells, LCL161 had significant antiproliferative effects at doses as low as 2μM and this was independent of Bcl-2 expression. Thus, LCL161 may be a useful agent in combination with paclitaxel to treat liver tumours.
authors: First Clinical Medical School and the Department of Gastroenterology and Hepatology of the First Hospital of Lanzhou University, Lanzhou 730000, China.
authors: Aiping
authors: A
authors: Tian
authors: Storr Liver Unit, University of Sydney, Westmead Millennium Institute, Westmead, NSW 2145, Australia.
authors: George S
authors: GS
authors: Wilson
authors: Storr Liver Unit, University of Sydney, Westmead Millennium Institute, Westmead, NSW 2145, Australia.
authors: Stefanus
authors: S
authors: Lie
authors: Storr Liver Unit, University of Sydney, Westmead Millennium Institute, Westmead, NSW 2145, Australia.
authors: Guang
authors: G
authors: Wu
authors: First Clinical Medical School and the Department of Gastroenterology and Hepatology of the First Hospital of Lanzhou University, Lanzhou 730000, China.
authors: Zenan
authors: Z
authors: Hu
authors: Storr Liver Unit, University of Sydney, Westmead Millennium Institute, Westmead, NSW 2145, Australia.
authors: Lionel
authors: L
authors: Hebbard
authors: School of Medicine, Deakin University, Pigdons Road, Waurn Ponds, VIC 3217, Australia.
authors: Wei
authors: W
authors: Duan
authors: Storr Liver Unit, University of Sydney, Westmead Millennium Institute, Westmead, NSW 2145, Australia.
authors: Jacob
authors: J
authors: George
authors: Storr Liver Unit, University of Sydney, Westmead Millennium Institute, Westmead, NSW 2145, Australia. Electronic address: liang.qiao@sydney.edu.au.
authors: Liang
authors: L
authors: Qiao
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D051034:Inhibitor of Apoptosis Proteins; C574246:LCL161; D019253:Proto-Oncogene Proteins c-bcl-2; D013844:Thiazoles; D017239:Paclitaxel
keywords: Combinatorial therapy; Hepatocellular carcinoma; JAK signalling; LCL161; Paclitaxel