The Acidic Tumor Microenvironment Promotes the Reconversion of Nitrite into Nitric Oxide: Towards a New and Safe Radiosensitizing Strategy
| Autor: | Olivier Feron, Géraldine Rath, Alexandra Smoos, Bernard Gallez, Françoise Frérart, Ahlam Meqor, Julie Saliez, Pierre Sonveaux, Agnès Noël, Nicolas Charlier, Chantal Dessy, Bénédicte F. Jordan |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Radiation-Sensitizing Agents Cancer Research Guanosine Mice Inbred Strains Pharmacology Nitric Oxide Nitric oxide Mice chemistry.chemical_compound Oxygen Consumption Arteriole medicine.artery Respiration medicine Animals Nitrite Nitrites Tumor microenvironment Catabolism Liver Neoplasms Oxygenation Hydrogen-Ion Concentration Vasodilation Oncology Biochemistry chemistry Blood Vessels |
| Zdroj: | Clinical Cancer Research. 14:2768-2774 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | 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 O2 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 O2 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 O2 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. |
| Databáze: | OpenAIRE |
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