title: Radiation-induced nitric oxide mitigates tumor hypoxia and radioresistance in a murine SCCVII tumor model.
abstract: Tumor hypoxia, which occurs mainly as a result of inadequate tissue perfusion in solid tumors, is a well-known challenge for successful radiotherapy. Recent evidence suggests that ionizing radiation (IR) upregulates nitric oxide (NO) production and that IR-induced NO has the potential to increase intratumoral circulation. However, the kinetics of NO production and the responsible isoforms for NO synthase in tumors exposed to IR remain unclear. In this study, we aimed to elucidate the mechanism by which IR stimulates NO production in tumors and the effect of IR-induced NO on tumor radiosensitivity. Hoechst33342 perfusion assay and electron spin resonance oxymetry showed that IR increased tissue perfusion and pO2 in tumor tissue. Immunohistochemical analysis using two different hypoxic probes showed that IR decreased hypoxic regions in tumors; treatment with a nitric oxide synthase (NOS) inhibitor, L-NAME, abrogated the effects of IR. Moreover, IR increased endothelial NOS (eNOS) activity without affecting its mRNA or protein expression levels in SCCVII-transplanted tumors. Tumor growth delay assay showed that L-NAME decreased the anti-tumor effect of fractionated radiation (10Gy×2). These results suggested that IR increased eNOS activity and subsequent tissue perfusion in tumors. Increases in intratumoral circulation simultaneously decreased tumor hypoxia. As a result, IR-induced NO increased tumor radiosensitivity. Our study provides a new insight into the NO-dependent mechanism for efficient fractionated radiotherapy.
authors.affiliation: Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan. nagane@vetmed.hokudai.ac.jp
authors.forename: Masaki
authors.initials: M
authors.lastname: Nagane
authors.forename: Hironobu
authors.initials: H
authors.lastname: Yasui
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamamori
authors.forename: Songji
authors.initials: S
authors.lastname: Zhao
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kuge
authors.forename: Nagara
authors.initials: N
authors.lastname: Tamaki
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kameya
authors.forename: Hideo
authors.initials: H
authors.lastname: Nakamura
authors.forename: Hirotada
authors.initials: H
authors.lastname: Fujii
authors.forename: Osamu
authors.initials: O
authors.lastname: Inanami
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D015687:Cell Hypoxia / Q000528:radiation effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005910:Glioma / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D000860:Hypoxia / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000096:biosynthesis / Q000528:radiation effects* / Q000627:therapeutic use*; D011836:Radiation Tolerance / Q000235:genetics*; D011839:Radiation, Ionizing; D015854:Up-Regulation / Q000235:genetics / Q000528:radiation effects
chemical_list: D009569:Nitric Oxide
keywords: 3-NT; 3-nitrotyrosine; ESR; Electron spin resonance; H33342; Hoechst33342; Ionizing radiation; L-NAME; LiNc-BuO; NG-nitro-L-arginine methyl ester; NO; NOS; Nitric oxide; Tumor reoxygenation; eNOS; electron spin resonance; endothelial nitric oxide synthase; iNOS; inducible nitric oxide synthase; lithium 5,9,14,18,23,27,32,36-octa-n-butoxy-2,3-naphthalocyanine; nNOS; neuronal nitric oxide synthase; nitric oxide