A small molecule inhibitor of XIAP induces apoptosis and synergises with vinorelbine and cisplatin in NSCLC

Abstract

Background: Evasion of apoptosis contributes to the pathogenesis of solid tumours including non-small cell lung cancer (NSCLC). Malignant cells resist apoptosis through over-expression of inhibitor of apoptosis proteins (IAPs), such as X-linked IAP (XIAP).Methods: A phenylurea-based small molecule inhibitor of XIAP, XIAP antagonist compound (XAC) 1396-11, was investigated preclincally to determine its ability to sensitise to clinically relevant cytotoxics, potentially allowing dose reduction while maintaining therapeutic efficacy.Results: XIAP protein expression was detected in six NSCLC cell lines examined. The cytotoxicity of XAC 1396-11 against cultured NSCLC cell lines in vitro was concentration-and time-dependent in both short-term and clonogenic assays. XAC 1396-11-induced apoptosis was confirmed by PARP cleavage and characteristic nuclear morphology. XAC 1396-11 synergised with vinorelbinecisplatin in H460 and A549 NSCLC cells. The mechanism of synergy was enhanced apoptosis, shown by increased cleavage of caspase-3 and PARP and by the reversal of synergy by a pan-caspase inhibitor. Synergy between XAC 1396-11 and vinorelbine was augmented by optimising drug scheduling with superior effects when XAC 1396-11 was administered before vinorelbine.Conclusion: These preclinical data suggest that XIAP inhibition in combination with vinorelbine holds potential as a therapeutic strategy in NSCLC. © 2010 Cancer Research UK All rights reserved.