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

Tian, A, Wilson, GS, Lie, S, Wu, G, Hu, Z, Hebbard, L, Duan, W, George, J and Qiao, L 2014, Synergistic effects of IAP inhibitor LCL161 and paclitaxel on hepatocellular carcinoma cells, Cancer Letters, vol. 351, no. 2, pp. 232-241, doi: 10.1016/j.canlet.2014.06.006.

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Title Synergistic effects of IAP inhibitor LCL161 and paclitaxel on hepatocellular carcinoma cells
Author(s) Tian, A
Wilson, GS
Lie, S
Wu, G
Hu, Z
Hebbard, L
Duan, WORCID iD for Duan, W
George, J
Qiao, L
Journal name Cancer Letters
Volume number 351
Issue number 2
Start page 232
End page 241
Total pages 10
Publisher Elsevier Ireland
Place of publication Shannon, County Clare, Ireland
Publication date 2014-09
ISSN 1872-7980
Keyword(s) Combinatorial therapy
Hepatocellular carcinoma
JAK signalling
Science & Technology
Life Sciences & Biomedicine
Summary 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.
Language eng
DOI 10.1016/j.canlet.2014.06.006
Field of Research 111299 Oncology and Carcinogenesis not elsewhere classified
Socio Economic Objective 920102 Cancer and Related Disorders
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2014, Elsevier
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Document type: Journal Article
Collection: School of Medicine
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