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

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    Authors
    Dean, Emma J
    Ward, Timothy H
    Pinilla, C
    Houghten, R
    Welsh, K
    Makin, Guy W J
    Ranson, Malcolm R
    Dive, Caroline
    Affiliation
    Department of Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester M20 4BX, England, UK [2] Derek Crowther Unit, Christie Hospital NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, England, UK.
    Issue Date
    2009-11-10
    
    Metadata
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    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 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 advance online publication, 10 November 2009; doi:10.1038/sj.bjc.6605418 www.bjcancer.com.
    Citation
    A small molecule inhibitor of XIAP induces apoptosis and synergises with vinorelbine and cisplatin in NSCLC. 2009: Br. J. Cancer
    Journal
    British Journal of Cancer
    URI
    http://hdl.handle.net/10541/87700
    DOI
    10.1038/sj.bjc.6605418
    PubMed ID
    19904270
    Type
    Article
    Language
    en
    ISSN
    1532-1827
    ae974a485f413a2113503eed53cd6c53
    10.1038/sj.bjc.6605418
    Scopus Count
    Collections
    All Christie Publications
    All Paterson Institute for Cancer Research
    Clinical and Experimental Pharmacology Group

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