title: Bevacizumab radiosensitizes non-small cell lung cancer xenografts by inhibiting DNA double-strand break repair in endothelial cells.
abstract: 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.
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China; Department of Oncology, Chengdu Military General Hospital, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Xue
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Lan
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China.
authors.forename: Jiazhuo
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Na
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China.
authors.forename: Lifei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Deng
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China. Electronic address: radyoulu@hotmail.com.
authors.forename: You
authors.initials: Y
authors.lastname: Lu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D000068258:Bevacizumab; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy / Q000379:methods*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000187:drug effects*; D004334:Drug Administration Schedule; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D011829:Radiation Dosage; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D011838:Radiation-Sensitizing Agents; D000068258:Bevacizumab
keywords: Bevacizumab; DNA double-strand break repair; Endothelial cells; Non-small cell lung cancer; Radiosensitivity