Small-molecule survivin inhibitor YM155 enhances radiosensitization in esophageal squamous cell carcinoma by the abrogation of G2 checkpoint and suppression of homologous recombination repair

Journal of Hematology & Oncology

Xinchen Sun⁶  Shengbin Dai²  Xizhi Zhang¹  Jianxin Ma³  Jia Liu⁶  Chi Zhang⁶  Hongcheng Zhu⁶  Liping Xu⁶  Xi Yang⁶  Jing Cai⁴  Jianchao Zheng⁵  Liangliang Zhan⁶  Jing Lu⁶  Hongyan Cheng⁶  Qin Qin⁶ 

[1] Department of Radiation Oncology, Subei People’s Hospital, Yangzhou, China;Department of Radiation Oncology, People’s Hospital of Tai Zhou, Taizhou, China;Department of Radiation Oncology, The No.2 People’s Hospital of Lian Yungang, Lianyungang, China;Department of Radiation Oncology, Nantong Tumor Hospital, Nantong, China;Department of Physiology, Nanjing Medical University, Nanjing, China;Department of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, No.300 Guangzhou Road, Nanjing 210029, China

关键词: Homologous recombination repair;    G2 checkpoint;    ESCC;    Radiosensitization;    YM155;    Survivin;   

Others  :  1144427
DOI  :  10.1186/s13045-014-0062-8

 received in 2014-05-15, accepted in 2014-08-06,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Qin et al.; licensee BioMed Central Ltd.

【 图 表 】

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