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

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Abstract

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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Authors and Affiliations

  1. Children’s Hospital Oakland Research Institute (CHORI), 5700 M.L.K. Jr Way, Oakland, CA, 94609, USA

    Marcel H. Fens, Sandra K. Larkin, Jung H. Suh & Frans A. Kuypers

  2. Department of Bioengineering, University of California San Diego (UCSD), 9500 Gilman Dr, La Jolla, CA, 92093, USA

    Pedro Cabrales

  3. EpicentRx, Inc., 800 W El Camino Real, Suite 180, Mountain View, CA, 94040, USA

    Jan Scicinski, Michelle Lybeck & Bryan Oronsky

  4. CFLS Data, 560 South Winchester Boulevard, San Jose, CA, 95128, USA

    Neil Oronsky

  5. InterWest Partners, 2710 Sand Hill Road #200, Menlo Park, CA, 94025, USA

    Arnold Oronsky

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  1. Marcel H. Fens
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  2. Pedro Cabrales
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Correspondence to Bryan Oronsky.

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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). https://doi.org/10.1007/s12032-016-0798-9

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