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: Masaki Nagane, Hironobu Yasui, Tohru Yamamori, Songji Zhao, Yuji Kuge, Nagara Tamaki, Hiromi Kameya, Hideo Nakamura, Hirotada Fujii, Osamu Inanami
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 437 Issue 3 Pg. 420-5 (Aug 02 2013) ISSN: 1090-2104 [Electronic] United States
• PMID: 23831468 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Nitric Oxide

Topics

• Animals
• Carcinoma, Squamous Cell (etiology, metabolism, prevention & control)
• Cell Hypoxia (radiation effects)
• Cell Line, Tumor
• Disease Models, Animal
• Female
• Glioma (etiology, metabolism, prevention & control)
• Hypoxia (pathology, prevention & control)
• Mice
• Mice, Inbred C3H
• Nitric Oxide (biosynthesis, radiation effects, therapeutic use)
• Radiation Tolerance (genetics)
• Radiation, Ionizing
• Up-Regulation (genetics, radiation effects)