title: YM155 down-regulates survivin and XIAP, modulates autophagy and induces autophagy-dependent DNA damage in breast cancer cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.affiliation: The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: S M
authors.initials: SM
authors.lastname: Cheng
authors.forename: Y C
authors.initials: YC
authors.lastname: Chang
authors.forename: C Y
authors.initials: CY
authors.lastname: Liu
authors.forename: J Y C
authors.initials: JY
authors.lastname: Lee
authors.forename: H H
authors.initials: HH
authors.lastname: Chan
authors.forename: C W
authors.initials: CW
authors.lastname: Kuo
authors.forename: K Y
authors.initials: KY
authors.lastname: Lin
authors.forename: S L
authors.initials: SL
authors.lastname: Tsai
authors.forename: S H
authors.initials: SH
authors.lastname: Chen
authors.forename: C F
authors.initials: CF
authors.lastname: Li
authors.forename: E
authors.initials: E
authors.lastname: Leung
authors.forename: J R
authors.initials: JR
authors.lastname: Kanwar
authors.forename: C C
authors.initials: CC
authors.lastname: Huang
authors.forename: J Y
authors.initials: JY
authors.lastname: Chang
authors.forename: C H A
authors.initials: CH
authors.lastname: Cheung
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D053148:Caspase 3; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D007770:L-Lactate Dehydrogenase; D008869:Microtubule-Associated Proteins; D009285:Naphthoquinones; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C107489:BIRC5 protein, human; C502070:MAP1LC3B protein, human; C496866:XIAP protein, human; C508053:ERBB2 protein, human; C523798:sepantronium