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

作者：Dean E J; Ward T; Pinilla C; Houghten R; Welsh K; Makin G; Ranson M; Dive C^*

来源：British Journal of Cancer, 2010, 102(1): 97-103.

DOI：10.1038/sj.bjc.6605418

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

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 vinorelbine +/- cisplatin 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. British Journal of Cancer (2010) 102, 97-103. doi:10.1038/sj.bjc.6605418 www.bjcancer.

• 出版日期2010-1-5
• 单位河北医科大学