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

Br J Pharmacol. 2015 Jan;172(1):214-34. doi: 10.1111/bph.12935. Epub 2014 Dec 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Inhibitor of Apoptosis Proteins / 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*

Substances

  • 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