期刊
CANCER LETTERS
卷 365, 期 1, 页码 79-88出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2015.05.011
关键词
Bevacizumab; Radiosensitivity; Non-small cell lung cancer; DNA double-strand break repair; Endothelial cells
类别
资金
- 11th 5-year plan for Technology Platform Construction of Innovative Drug Research and Development of China [2012ZX09303012-002]
- National Natural Science Foundation of China [81172131, 81472196]
- Chinese Society of Clinical Oncology [H11-050]
The aims of this study were to evaluate the effects of biweekly bevacizumab administration on a tumor microenvironment and to investigate the mechanisms of radiosensitization that were induced by it. Briefly, bevacizumab was administered intravenously to Balb/c nude mice bearing non-small cell lung cancer (NSCLC) H1975 xenografts; in addition, bevacizumab was added to NSCLC or endothelial cells (ECs) in vitro, followed by irradiation (IR), The anti-tumor efficacy, anti-angiogenic efficacy and repair of DNA double-strand breaks (DSBs) were evaluated. The activation of signaling pathways was determined using immunoprecipitation (IP) and WB analyses. Finally, biweekly bevacizumab administration inhibited the growth of H1975 xenografts and induced vascular normalization periodically. Bevacizumab more significantly increased cellular DSB and EC apoptosis when administered 1 h prior to 12 Gy/1f IR than when administered 5 days prior to IR, thereby inhibiting tumor angiogenesis and growth. In vitro, bevacizumab more effectively increased DSBs and apoptosis prior to IR and inhibited the clonogenic survival of ECs but not NSCLC cells. Using IP and WB analyses, we confirmed that bevacizumab can directly inhibit the phosphorylation of components of the VEGR2/PI3K/Akt/DNA-PKcs signaling pathway that are induced by IR in ECs. In conclusion, bevacizumab radiosensitizes NSCLC xenografts mainly by inhibiting DSB repair in ECs rather than by inducing vascular normalization. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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