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

E. J. Dean, T. Ward, C. Pinilla, R. Houghten, K. Welsh, G. Makin, M. Ranson, C. Dive

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)97-103
Number of pages7
JournalBritish Journal of Cancer
Volume102
Issue number1
DOIs
StatePublished - Jan 2010
Externally publishedYes

Keywords

  • Apoptosis, non-small cell lung cancer (NSCLC)
  • XAC 1396-11
  • XIAP
  • XIAP antagonist compound

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