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Med Oncol (2016) 33:85DOI 10.1007/s12032-016-0798-9
http://crossmark.crossref.org/dialog/?doi=10.1007/s12032-016-0798-9&domain=pdf
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Targeting tumor hypoxia with the epigenetic anticancer agent, RRx-001: a superagonist of nitric oxide generation
Marcel H. Fens1 Pedro Cabrales2 Jan Scicinski3 Sandra K. Larkin1
Jung H. Suh1 Frans A. Kuypers1 Neil Oronsky4 Michelle Lybeck3
Arnold Oronsky5 Bryan Oronsky3
Received: 31 May 2016 / Accepted: 15 June 2016 / Published online: 4 July 2016 Springer Science+Business Media New York 2016
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 rst 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 NOH2O2 trigger is indirectly responsible for the observed tumoricidal activity
of RRx-001 since NO is known to inhibit mitochondrial respiration.
Keywords Oncology RRx-001 Nitric oxide
Deoxyhemoglobin Nitric oxide synthase
Introduction
Birds do it, bees do it. Even educated eas do it Cole Porter, Lets do it
With apologies to Cole Porter and Ella Fitzgerald, birds, bees and eas are not the only ones who do it. Bacteria, arthropods, molluscs, annelids and humans, to name a few other species, also do itthat is, they reduce the anion nitrite (NO2-) to nitric oxide (NO) via the nitrite reductase activity of deoxyhemoglobin (deoxyHb) [1]. Unlike nitric
& Bryan Oronsky [email protected]
Marcel H. Fens [email protected]
Pedro Cabrales [email protected]
Jan Scicinski [email protected]
Sandra K. Larkin [email protected]
Jung H. Suh [email protected]
Frans A. Kuypers [email protected]
Neil Oronsky [email protected]
Michelle Lybeck [email protected]
Arnold Oronsky [email protected]
1 Childrens Hospital Oakland Research Institute (CHORI),5700 M.L.K. Jr Way, Oakland, CA 94609, USA
2 Department of Bioengineering, University of California San Diego (UCSD), 9500 Gilman Dr, La Jolla, CA 92093, USA
3 EpicentRx, Inc.,...