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9 a.m. - 4 p.m.
Phone: (843) 766-6635
Main Library
9 a.m. - 6 p.m.
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Folly Beach Library
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John L. Dart Library
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St. Paul's/Hollywood Library
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A small molecule inhibitor of XIAP induces apoptosis and synergises with vinorelbine and cisplatin in NSCLC.
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- Author(s): Dean, E. J.1; Ward, T.2; Pinilla, C.3; Houghten, R.3; Welsh, K.4; Makin, G.2; Ranson, M.2; Dive, C.2
- Source:
British Journal of Cancer. 1/4/2010, Vol. 102 Issue 1, p97-103. 7p. 1 Chart, 4 Graphs.- Subject Terms:
*LUNG cancer; *CARCINOGENESIS; *APOPTOSIS; *VINORELBINE; *CISPLATIN; *GENE expression; *AMINES; *ANTINEOPLASTIC agents; *CELL lines; *COMPARATIVE studies; *DRUG synergism; *DRUG administration; *CLINICAL drug trials; *LUNG tumors; *RESEARCH methodology; *MEDICAL cooperation; *PROTEINS; *RESEARCH; *RESEARCH funding; *VINBLASTINE; *EVALUATION research; *CYTOTOXINS; *COLONY-forming units assay; *CHEMICAL inhibitors; *PHARMACODYNAMICS - Source:
- Additional Information
- 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. [ABSTRACT FROM AUTHOR] - Abstract: Copyright of British Journal of Cancer is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Abstract:
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