國家衛生研究院 NHRI:Item 3990099045/9788
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    题名: Down-regulation of survivin enhances sensitivity to BPROL075 in human cancer cells via caspase-independent mechanisms
    作者: Cheung, CHA;Chang, CY;Hsieh, HP;Chang, JY
    贡献者: National Institute of Cancer Research;Institute of Biotechnology and Pharmaceutical Research
    摘要: BPR0L075 [6-methoxy-3-(3',4',5'-trimethoxy-benzoyl)-1H-indole] is a novel anti-mitotic compound. We pervious have demonstrated that this compound could inhibit tubulin polymerization and induces mitochondrial-dependent apoptosis in various human cancer cells with different multi-drug resistance (MDR) status (Kuo et al., Cancer Research, 2004). Over-expression of an anti-apoptotic molecule, survivin, causes drug-resistance in various cancers. Survivin inhibits apoptosis by interfering caspase-3 and promotes cell growth by stabilizing microtubule networks. Here, we determined the effects of down-regulation of survivin in BPR0L075 (L075) treatment. Western blot analysis and RT-PCR show that survivin expression was up-regulated in both human KB and HONE-1 cancer cells in response to L075 treatment. Down-regulation of survivin by siRNA induced hyper-sensitivity to L075 in KB and re-stored sensitivity to L075 in KB-derived L075-resistant KB-L30 cancer cells. At the molecular level, western blot analysis and immunofluorescence microscopy reveal that down-regulation of survivin induced changes in microtubule dynamics in both KB and KB-L30 cells. Surprisingly, down-regulation of survivin did not enhance the activity of caspase-3 in L075 therapy. Instead, down-regulation of survivin induced translocation of the apoptosis-inducing factor (AIF) from cytoplasm to nucleus. In summary, down-regulation of survivin improved drug sensitivity to L075 in both KB and L075-resistant KB-L30 cancer cells, through a tubulin-dependent and caspase-independent mechanism. Our data suggest that combining BPR0L075 and survivin inhibitor may give better clinical outcome than the use of BPR0L075 monotherapy in future clinical trials.
    日期: 2009-05
    關聯: Cancer Research. 2009 May;69:Abstract number 5542.
    Link to: http://cancerres.aacrjournals.org/content/69/9_Supplement/5542.short
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0008-5472&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000209702604137
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