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

Marcel H. Fens, Pedro Cabrales, Jan Scicinski, Sandra K. Larkin, Jung H. Suh, Frans A. Kuypers, Neil Oronsky, Michelle Lybeck, Arnold Oronsky, Bryan Oronsky

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number85
JournalMedical Oncology
Volume33
Issue number8
DOIs
StatePublished - Aug 1 2016
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Hematology

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