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.
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Authors | 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, J Y Chang, C H A Cheung |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 172
Issue 1
Pg. 214-34
(Jan 2015)
ISSN: 1476-5381 [Electronic] England |
PMID | 25220225
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2014 The British Pharmacological Society. |
Chemical References |
- Antineoplastic Agents
- BIRC5 protein, human
- Imidazoles
- Inhibitor of Apoptosis Proteins
- MAP1LC3B protein, human
- Microtubule-Associated Proteins
- Naphthoquinones
- RNA, Small Interfering
- Receptors, Estrogen
- Survivin
- X-Linked Inhibitor of Apoptosis Protein
- XIAP protein, human
- L-Lactate Dehydrogenase
- ERBB2 protein, human
- Receptor, ErbB-2
- Caspase 3
- sepantronium
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Topics |
- Antineoplastic Agents
(pharmacology)
- Autophagy
(drug effects)
- Breast Neoplasms
(metabolism)
- Caspase 3
(metabolism)
- Cell Line, Tumor
- Cell Survival
(drug effects)
- DNA Damage
- Down-Regulation
(drug effects)
- Humans
- Imidazoles
(pharmacology)
- Inhibitor of Apoptosis Proteins
(genetics, metabolism)
- L-Lactate Dehydrogenase
(metabolism)
- Microtubule-Associated Proteins
(metabolism)
- Naphthoquinones
(pharmacology)
- RNA, Small Interfering
(genetics)
- Receptor, ErbB-2
(metabolism)
- Receptors, Estrogen
(metabolism)
- Survivin
- X-Linked Inhibitor of Apoptosis Protein
(metabolism)
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