國家衛生研究院 NHRI:Item 3990099045/8471
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    題名: YM155 down-regulates survivin and XIAP, modulates autophagy and induces autophagy-dependent DNA damage in breast cancer cells
    作者: Cheng, SM;Chang, YC;Liu, CY;Lee, JYC;Chan, HH;Kuo, CW;Lin, KY;Tsai, SL;Chen, SH;Li, CF;Leung, E;Kanwar, JR;Huang, CC;Chang, JY;Cheung, CHA
    貢獻者: National Institute of Cancer Research
    摘要: Background and Purpose: The aim of this study was to determine the potency and molecular mechanism of action of YM155, a first-in-class survivin inhibitor that is currently under phase I/II clinical investigations, in various drug-resistant breast cancers including the oestrogen receptor positive (ER+) tamoxifen-resistant breast cancer and the caspase-3-deficient breast cancer. Experimental Approach: The potency of YM155 in SK-BR-3, MDA-MB-231, MCF7 and its tamoxifen-resistant sublines, TamR6, TamR7, TamR8, TamC3 and TamC6, were determined by MTT assay. Western blot analysis, flow cytometric analysis, reverse transcription-PCR, fluorescent microscopy and comet assay were used to determine the molecular mechanism of action of YM155 in different breast cancer cell lines. Key Results: YM155 was equally potent towards the parental ER+/caspase-3-deficient MCF7 breast cancer cells and its tamoxifen-resistant sublines in vitro. The ER-/HER2+ SK-BR-3 breast cancer cells and the triple-negative/caspase-3-expressing metastatic aggressive MDA-MB-231 breast cancer cells were also sensitive to YM155 with IC50 values in the low nanomolar range. Targeting survivin by YM155 modulated autophagy, induced autophagy-dependent caspase-7 activation and autophagy-dependent DNA damage in breast cancer cells. Interestingly, YM155 also induced XIAP degradation and the degradation of XIAP might play an important role in YM155-induced autophagy in breast cancer cells. Conclusions and Implications: YM155 is a potent survivin inhibitor that has potential for the management of various breast cancer subtypes regardless of the expression of ER, HER2 and caspase-3. Importantly, this study provides new insights into YM155's molecular mechanism of action and therapeutic potential in the treatment of tamoxifen-resistant breast cancer.
    日期: 2015-01
    關聯: British Journal of Pharmacology. 2015 Jan;172(1):214-234.
    Link to: http://dx.doi.org/10.1111/bph.12935
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0007-1188&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000346657300016
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84919630479
    顯示於類別:[張俊彥] 期刊論文

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