YM155 down-regulates survivin and XIAP, modulates autophagy and induces autophagy-dependent DNA damage in breast cancer cells

S. M. Cheng, Y. C. Chang, C. Y. Liu, J. Y.C. Lee, H. H. Chan, C. W. Kuo, K. Y. Lin, S. L. Tsai, S. H. Chen, C. F. Li, E. Leung, J. R. Kanwar, C. C. Huang, Jang-Yang Chang, Chun-Hei Cheung

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Abstract

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.

Original languageEnglish
Pages (from-to)214-234
Number of pages21
JournalBritish Journal of Pharmacology
Volume172
Issue number1
DOIs
Publication statusPublished - 2015 Jan 1

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Autophagy
DNA Damage
Down-Regulation
Breast Neoplasms
Tamoxifen
Caspase 3
Triple Negative Breast Neoplasms
Caspase 7
Comet Assay
Estrogen Receptors
Action Potentials
Inhibitory Concentration 50
Reverse Transcription
Microscopy
Western Blotting
Cell Line
Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

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, Jang-Yang ; Cheung, Chun-Hei. / YM155 down-regulates survivin and XIAP, modulates autophagy and induces autophagy-dependent DNA damage in breast cancer cells. In: British Journal of Pharmacology. 2015 ; Vol. 172, No. 1. pp. 214-234.
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title = "YM155 down-regulates survivin and XIAP, modulates autophagy and induces autophagy-dependent DNA damage in breast cancer cells",
abstract = "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.",
author = "Cheng, {S. M.} and Chang, {Y. C.} and Liu, {C. Y.} and Lee, {J. Y.C.} and Chan, {H. H.} and Kuo, {C. W.} and Lin, {K. Y.} and Tsai, {S. L.} and Chen, {S. H.} and Li, {C. F.} and E. Leung and Kanwar, {J. R.} and Huang, {C. C.} and Jang-Yang Chang and Chun-Hei Cheung",
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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, J-Y & Cheung, C-H 2015, 'YM155 down-regulates survivin and XIAP, modulates autophagy and induces autophagy-dependent DNA damage in breast cancer cells', British Journal of Pharmacology, vol. 172, no. 1, pp. 214-234. https://doi.org/10.1111/bph.12935

YM155 down-regulates survivin and XIAP, modulates autophagy and induces autophagy-dependent DNA damage in breast cancer cells. / 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, Jang-Yang; Cheung, Chun-Hei.

In: British Journal of Pharmacology, Vol. 172, No. 1, 01.01.2015, p. 214-234.

Research output: Contribution to journalArticle

TY - JOUR

T1 - YM155 down-regulates survivin and XIAP, modulates autophagy and induces autophagy-dependent DNA damage in breast cancer cells

AU - Cheng, S. M.

AU - Chang, Y. C.

AU - Liu, C. Y.

AU - Lee, J. Y.C.

AU - Chan, H. H.

AU - Kuo, C. W.

AU - Lin, K. Y.

AU - Tsai, S. L.

AU - Chen, S. H.

AU - Li, C. F.

AU - Leung, E.

AU - Kanwar, J. R.

AU - Huang, C. C.

AU - Chang, Jang-Yang

AU - Cheung, Chun-Hei

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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.

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