Activated Macrophages as a Novel Determinant of Tumor Cell Radioresponse: The Role of Nitric Oxide-Mediated Inhibition of Cellular Respiration and Oxygen Sparing

Journal Article · Thu Apr 15 00:00:00 EDT 2010 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2009.10.047· OSTI ID:21372222

Heng, Jiang ^[1]; Verovski, Valeri N ^[2]; Sonveaux, Pierre ^[3]; Jordan, Benedicte F ^[4]; Law, Kalun; Monsaert, Christinne ^[1]; Van den Berge, Dirk L; Verellen, Dirk ^[2]; Feron, Olivier ^[3]; Gallez, Bernard ^[4]; Storme, Guy A ^[1]

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1. Vrije Universiteit Brussel, Cancer Research Unit, Brussels (Belgium)
2. UZ Brussel, Oncologisch Centrum, Radiotherapie, Universite catholique de Louvain, Brussels (Belgium)
3. Unit of Pharmacology and Therapeutics, Universite catholique de Louvain, Brussels (Belgium)
4. Unit of Biomedical Magnetic Resonance, Universite catholique de Louvain, Brussels (Belgium)

Purpose: Nitric oxide (NO), synthesized by the inducible nitric oxide synthase (iNOS), is known to inhibit metabolic oxygen consumption because of interference with mitochondrial respiratory activity. This study examined whether activation of iNOS (a) directly in tumor cells or (b) in bystander macrophages may improve radioresponse through sparing of oxygen. Methods and Materials: EMT-6 tumor cells and RAW 264.7 macrophages were exposed to bacterial lipopolysaccharide plus interferon-gamma, and examined for iNOS expression by reverse transcription polymerase chain reaction, Western blotting and enzymatic activity. Tumor cells alone, or combined with macrophages were subjected to metabolic hypoxia and analyzed for radiosensitivity by clonogenic assay, and for oxygen consumption by electron paramagnetic resonance and a Clark-type electrode. Results: Both tumor cells and macrophages displayed a coherent picture of iNOS induction at transcriptional/translational levels and NO/nitrite production, whereas macrophages showed also co-induction of the inducible heme oxygenase-1, which is associated with carbon monoxide (CO) and bilirubin production. Activation of iNOS in tumor cells resulted in a profound oxygen sparing and a 2.3-fold radiosensitization. Bystander NO-producing, but not CO-producing, macrophages were able to block oxygen consumption by 1.9-fold and to radiosensitize tumor cells by 2.2-fold. Both effects could be neutralized by aminoguanidine, a metabolic iNOS inhibitor. An improved radioresponse was clearly observed at macrophages to tumor cells ratios ranging between 1:16 to 1:1. Conclusions: Our study is the first, as far as we are aware, to provide evidence that iNOS may induce radiosensitization through oxygen sparing, and illuminates NO-producing macrophages as a novel determinant of tumor cell radioresponse within the hypoxic tumor microenvironment.

• OSTI ID: 21372222
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Vol. 76, Issue 5; Other Information: DOI: 10.1016/j.ijrobp.2009.10.047; PII: S0360-3016(09)03518-4; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
ANOXIA
INHIBITION
MACROPHAGES
MITOCHONDRIA
NITRIC OXIDE
OXYGEN
RADIOSENSITIVITY
RESPIRATION
TUMOR CELLS
ANIMAL CELLS
CELL CONSTITUENTS
CHALCOGENIDES
CONNECTIVE TISSUE CELLS
ELEMENTS
NITROGEN COMPOUNDS
NITROGEN OXIDES
NONMETALS
OXIDES
OXYGEN COMPOUNDS
PHAGOCYTES
SENSITIVITY
SOMATIC CELLS