Synergistic effects of IAP inhibitor LCL161 and paclitaxel on hepatocellular carcinoma cells

Tian, Aiping, Wilson, George S., Lie, Stefanus, Wu, Guang, Hu, Zenan, Hebbard, Lionel, Duan, Wei, George, Jacob, and Qiao, Liang (2014) Synergistic effects of IAP inhibitor LCL161 and paclitaxel on hepatocellular carcinoma cells. Cancer Letters, 351 (2). pp. 232-241.

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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 ≥100 μM. 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 2 μM and this was independent of Bcl-2 expression. Thus, LCL161 may be a useful agent in combination with paclitaxel to treat liver tumours.

Item ID: 40186
Item Type: Article (Research - C1)
ISSN: 1872-7980
Keywords: LCL161; hepatocellular carcinoma; JAK signalling; paclitaxel; combinatorial therapy
Funders: Robert W. Storr Bequest to the Sydney Medical Foundation of the University of Sydney, National Health and Medical Research Council of Australia (NHMRC)., Cancer Council NSW (CC), Sydney West Translational Cancer Research Centre Partner Program, Cancer Institute NSW (CI)
Projects and Grants: NHMRC Program Grant 1053206, NHMRC Project Grant APP1047417, CC Grant APP1070076, CC Grant APP1069733, CI Career Development and Support Fellowship Future Research Leader Grant 08/FRL/1-04
Date Deposited: 26 Aug 2015 02:53
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1112 Oncology and Carcinogenesis > 111201 Cancer Cell Biology @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920102 Cancer and Related Disorders @ 100%
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