title: Small-molecule survivin inhibitor YM155 enhances radiosensitization in esophageal squamous cell carcinoma by the abrogation of G2 checkpoint and suppression of homologous recombination repair.
abstract: BACKGROUND
  Survivin is overexpressed in cancer cells and plays a crucial role in apoptosis evasion. YM155, a small-molecule inhibitor of survivin, could enhance the cytotoxicity of various DNA-damaging agents. Here, we evaluated the radiosensitizaion potential of YM155 in human esophageal squamous cell carcinoma (ESCC).
  
  
  METHODS
  Cell viability was determined by CCK8 assay. The radiosensitization effect of YM155 was evaluated by clonogenic survival and progression of tumor xenograft. Cell cycle progression was determined by flow cytometric analysis. Radiation-induced DNA double strand break (DSB) and homologous recombination repair (HRR) were detected by the staining of γ-H2AX and RAD51, respectively. Expression of survivin and cell cycle regulators was detected by Western blot analysis.
  
  
  RESULTS
  YM155 induced radiosensitization in ESCC cell lines Eca109 and TE13, associated with the abrogation of radiation induced G2/M checkpoint, impaired Rad51 focus formation, and the prolongation of γ-H2AX signaling. G2/M transition markers, including the activation of cyclinB1/Cdc2 kinase and the suppression of Cdc2 Thr14/Tyr15 phosphorylation were induced by YM155 in irradiated cells. The combination of YM155 plus irradiation delayed the growth of ESCC tumor xenografts to a greater extent compared with either treatment modality alone.
  
  
  CONCLUSIONS
  Our findings suggest that the abrogation of G2 checkpoint and the inhibition of HRR contribute to radiosensitization by YM155 in ESCC cells.
authors.forename: Qin
authors.initials: Q
authors.lastname: Qin
authors.forename: Hongyan
authors.initials: H
authors.lastname: Cheng
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: Liangliang
authors.initials: L
authors.lastname: Zhan
authors.forename: Jianchao
authors.initials: J
authors.lastname: Zheng
authors.forename: Jing
authors.initials: J
authors.lastname: Cai
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.forename: Liping
authors.initials: L
authors.lastname: Xu
authors.forename: Hongcheng
authors.initials: H
authors.lastname: Zhu
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Jianxin
authors.initials: J
authors.lastname: Ma
authors.forename: Xizhi
authors.initials: X
authors.lastname: Zhang
authors.forename: Shengbin
authors.initials: S
authors.lastname: Dai
authors.forename: Xinchen
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009285:Naphthoquinones / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D059767:Recombinational DNA Repair / Q000187:drug effects*; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D011838:Radiation-Sensitizing Agents; D000077022:Survivin; C523798:sepantronium