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




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Journal of Hematology and Oncology

, 7:62

Novel agents for cancer therapy

Abstract

BackgroundSurvivin 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.

MethodsCell 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.

ResultsYM155 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.

ConclusionsOur findings suggest that the abrogation of G2 checkpoint and the inhibition of HRR contribute to radiosensitization by YM155 in ESCC cells.

KeywordsSurvivin YM155 Radiosensitization ESCC G2 checkpoint Homologous recombination repair Electronic supplementary materialThe online version of this article doi:10.1186-s13045-014-0062-8 contains supplementary material, which is available to authorized users.

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Autor: Qin Qin - Hongyan Cheng - Jing Lu - Liangliang Zhan - Jianchao Zheng - Jing Cai - Xi Yang - Liping Xu - Hongcheng Zhu - C

Fuente: https://link.springer.com/







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