The acidic tumor microenvironment promotes the reconversion of nitrite into nitric oxide: towards a new and safe radiosensitizing strategy
Open accessAbstract
PURPOSE: The biological status of nitrite recently evolved from an inactive end product of nitric oxide catabolism to the largest intravascular and tissue storage of nitric oxide (NO). Although low partial O(2) pressure favors enzymatic reconversion of nitrite into NO, low pH supports a nonenzymatic pathway. Because hypoxia and acidity are characteristics of the tumor microenvironment, we examined whether nitrite injection could preferentially lead to NO production in tumors and influence response to treatments. EXPERIMENTAL DESIGN: The effects of nitrite were evaluated on arteriole vasorelaxation, tumor cell respiration and tumor blood flow, oxygenation, and response to radiotherapy. RESULTS: We first showed that a small drop in pH (-0.6 pH unit) favored the production of bioactive NO from nitrite by documenting a higher cyclic guanosine 3',5'-monophosphate-dependent arteriole vasorelaxation. We then documented that an i.v. bolus injection of nitrite to tumor-bearing mice led to a transient increase in partial O(2) pressure in tumor but not in healthy tissues. Blood flow measurements failed to reveal an effect of nitrite on tumor perfusion, but we found that O(2) consumption by nitrite-exposed tumor cells was decreased at acidic pH. Finally, we showed that low dose of nitrite could sensitize tumors to radiotherapy, leading to a significant growth delay and an increase in mouse survival (versus irradiation alone). CONCLUSIONS: This study identified low pH condition (encountered in many tumors) as an exquisite environment that favors tumor-selective production of NO in response to nitrite systemic injection. This work opens new perspectives for the use of nitrite as a safe and clinically applicable radiosensitizing modality.
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Nitrite selectively induces a transient increase in tumor partial O2 pressure (pO2).
“It was found that nitrite selectively induce a transient increase in tumor partial O2 pressure (pO2), which improved the efficacy of radiotherapy.”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [262]
Nitrite-induced transient increase in tumor pO2 improved the efficacy of radiotherapy.
“It was found that nitrite selectively induce a transient increase in tumor partial O2 pressure (pO2), which improved the efficacy of radiotherapy.”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [262]
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Inorganic nitrite therapy: historical perspective and future directions
Kevil, C. G., Kolluru, G. K., Pattillo, C. B., & Giordano, T. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.04.042 · Cited by 113 · see citing works
- Authors
- Frérart, F., Sonveaux, P., Rath, G., Smoos, A., Meqor, A., Charlier, N., Jordan, B. F., Saliez, J., Noël, A., Dessy, C., Gallez, B., & Feron, O.
- Affiliations
- 1Pharmacology and Therapeutics, Université catholique de Louvain, UCL-FATH and Unit of
- UCLouvain (BE)
- 2Biomedical Magnetic Resonance, Université catholique de Louvain, UCL-REMA, Brussels, Belgium; and
- 3Laboratory of Tumor and Developmental Biology, University of Liège, Tour de Pathologie (B23), Sart-Tilman, Belgium
- Venue
- Clinical Cancer Research
- Published
- 2008-05-01
- Volume
- 14
- Issue
- 9
- Pages
- 2768-2774
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2153330586
- Cited by
- 49
- References
- 47
- Citations by year
- 2026: 2 · 2025: 1 · 2023: 2 · 2022: 4 · 2021: 1 · 2020: 3 · 2019: 4 · 2018: 3 · 2017: 4 · 2016: 2 · 2015: 3 · 2014: 2 · 2013: 3 · 2012: 3
- FWCI
- 1.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Liège) (submittedVersion)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- nitrite, nitric oxide, tumor acidosis, radiosensitization, radiotherapy, tumor hypoxia, tumor oxygenation, tumor cell respiration, vasorelaxation, cyclic GMP, tumor perfusion
- MeSH terms
- Animals, Blood Vessels, Hydrogen-Ion Concentration, Liver Neoplasms, Male, Mice, Inbred Strains, Nitric Oxide, Nitrites, Oxygen Consumption, Radiation-Sensitizing Agents, Vasodilation, Mice
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