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.

• 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)
• 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

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)