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Ref Type Journal Article
PMID (24976294)
Authors Tian A, Wilson GS, Lie S, Wu G, Hu Z, Hebbard L, Duan W, George J, Qiao L
Title Synergistic effects of IAP inhibitor LCL161 and paclitaxel on hepatocellular carcinoma cells.
Journal Vol Issue Date Pages Journal Short Title
Cancer letters 351 2 2014 Sep 01 232-41 Cancer Lett
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
LCL161 LCL161 0 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
LCL161 LCL-161|LCL 161 SMAC Mimetic 8 LCL161 is a SMAC mimetic that inhibits Inhibitor of Apoptosis Protein (IAP) family proteins, potentially leading to increased tumor cell death (PMID: 21681929, PMID: 24976294, PMID: 25113756).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References