YM155 down‐regulates survivin and XIAP, modulates autophagy and induces autophagy‐dependent DNA damage in breast cancer cells. (1st December 2014)

• Record Type: Journal Article
• Authors: Cheng, S M; Chang, Y C; Liu, C Y; Lee, J Y C; Chan, H H; Kuo, C W; Lin, K Y; Tsai, S L; Chen, S H; Li, C F; Leung, E; Kanwar, J R; Huang, C C; Chang, J Y; Cheung, C H A
• Is Part Of: British journal of pharmacology. Volume 172:Number 1(2015:Jan.)
• Page Start: 214
• Page End: 234
• Publication Date: 2014-12-01
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12935
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12935-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>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<sup>+</sup>) tamoxifen‐resistant breast cancer and the caspase‐3‐deficient breast cancer.</p> </sec> <sec id="bph12935-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>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.</p> </sec> <sec id="bph12935-sec-0003" sec-type="section"> <title>Key Results</title> <p>YM155 was equally potent towards the parental ER<sup>+</sup>/caspase‐3‐deficient MCF7 breast cancer cells and its tamoxifen‐resistant sublines <italic>in vitro</italic>. The ER<sup>−</sup>/HER2<sup>+</sup> 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 IC<sub>50</sub> 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.</p> </sec> <sec id="bph12935-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>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.</p> </sec> </abstract>