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BMS-345541 sensitizes MCF-7 breast cancer cells to ionizing radiation by selective inhibition of homologous recombinational repair of DNA double-strand breaks.

Abstract
Our study was to elucidate the mechanisms whereby BMS-345541 (BMS, a specific IκB kinase β inhibitor) inhibits the repair of DNA double-strand breaks (DSBs) and evaluate whether BMS can sensitize MCF-7 breast cancer cells (MCF-7 cells) to ionizing radiation (IR) in an apoptosis-independent manner. In this study, MCF-7 cells were exposed to IR in vitro and in vivo with or without pretreatment of BMS. The effects of BMS on the repair of IR-induced DSBs by homologous recombination (HR) and non-homologous end-joining (NHEJ) were analyzed by the DR-GFP and EJ5-GFP reporter assays and IR-induced γ-H2AX, 53BP1, Brca1 and Rad51 foci assays. The mechanisms by which BMS inhibits HR were examined by microarray analysis and quantitative reverse transcription PCR. The effects of BMS on the sensitivity of MCF-7 cells to IR were determined by MTT and clonogenic assays in vitro and tumor growth inhibition in vivo in a xenograft mouse model. The results showed that BMS selectively inhibited HR repair of DSBs in MCF-7 cells, most likely by down-regulation of several genes that participate in HR. This resulted in a significant increase in the DNA damage response that sensitizes MCF-7 cells to IR-induced cell death in an apoptosis-independent manner. Furthermore, BMS treatment sensitized MCF-7 xenograft tumors to radiation therapy in vivo in an association with a significant delay in the repair of IR-induced DSBs. These data suggest that BMS is a novel HR inhibitor that has the potential to be used as a radiosensitizer to increase the responsiveness of cancer to radiotherapy.
AuthorsLixian Wu, Lijian Shao, Manna Li, Junying Zheng, Junru Wang, Wei Feng, Jianhui Chang, Yan Wang, Martin Hauer-Jensen, Daohong Zhou
JournalRadiation research (Radiat Res) Vol. 179 Issue 2 Pg. 160-70 (Feb 2013) ISSN: 1938-5404 [Electronic] United States
PMID23259762 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • 4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline
  • Imidazoles
  • Protein Kinase Inhibitors
  • Quinoxalines
  • I-kappa B Kinase
Topics
  • Animals
  • Apoptosis (drug effects, radiation effects)
  • Breast Neoplasms (pathology)
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • DNA Breaks, Double-Stranded (drug effects, radiation effects)
  • DNA Repair (drug effects, genetics, radiation effects)
  • Dose-Response Relationship, Drug
  • Down-Regulation (drug effects, radiation effects)
  • Female
  • Gene Expression Regulation, Neoplastic (drug effects, radiation effects)
  • Homologous Recombination (drug effects, radiation effects)
  • Humans
  • I-kappa B Kinase (antagonists & inhibitors)
  • Imidazoles (pharmacology)
  • Mice
  • Protein Kinase Inhibitors (pharmacology)
  • Quinoxalines (pharmacology)

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