Targeting tumor hypoxia with the epigenetic anticancer agent, RRx-001: a superagonist of nitric oxide generation


This study reveals a novel interaction between deoxyhemoglobin, nitrite and the non-toxic compound, RRx-001, to generate supraphysiologic levels of nitric oxide (NO) in blood. We characterize the nitrite reductase activity of deoxyhemoglobin, which in the presence of bound RRx-001 reduces nitrite at a much faster rate, leading to markedly increased NO generation. These data expand on the paradigm that hemoglobin generates NO via nitrite reduction during hypoxia and ischemia when nitric oxide synthase (NOS) function is limited. Here, we demonstrate that RRx-001 greatly enhances NO generation from nitrite reduction. RRx-001 is thus the first example of a functional superagonist for nitrite reductase. We hypothesize that physiologically this reaction releases the potentially cytotoxic effector NO selectively in hypoxic tumor regions. It may be that a binary NO–H2O2 trigger is indirectly responsible for the observed tumoricidal activity of RRx-001 since NO is known to inhibit mitochondrial respiration.

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Author’s contributions

The authors state that all authors (MH, PC, JS, SK, JS, FK, NO, ML, AO and BO) contributed to all stages of work behind this manuscript: idea conception, design and execution of the studies, analysis, drafting, writing and editing of the manuscript.

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Correspondence to Bryan Oronsky.

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The authors disclose that EpicentRx Inc. has funded parts of this research.

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Fens, M.H., Cabrales, P., Scicinski, J. et al. Targeting tumor hypoxia with the epigenetic anticancer agent, RRx-001: a superagonist of nitric oxide generation. Med Oncol 33, 85 (2016).

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  • Oncology
  • RRx-001
  • Nitric oxide
  • Deoxyhemoglobin
  • Nitric oxide synthase