title: Targeting tumor hypoxia with the epigenetic anticancer agent, RRx-001: a superagonist of nitric oxide generation.
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.
authors.affiliation: Children's Hospital Oakland Research Institute (CHORI), 5700 M.L.K. Jr Way, Oakland, CA, 94609, USA.
authors.forename: Marcel H
authors.initials: MH
authors.lastname: Fens
authors.affiliation: Department of Bioengineering, University of California San Diego (UCSD), 9500 Gilman Dr, La Jolla, CA, 92093, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Cabrales
authors.affiliation: EpicentRx, Inc., 800 W El Camino Real, Suite 180, Mountain View, CA, 94040, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Scicinski
authors.affiliation: Children's Hospital Oakland Research Institute (CHORI), 5700 M.L.K. Jr Way, Oakland, CA, 94609, USA.
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Larkin
authors.affiliation: Children's Hospital Oakland Research Institute (CHORI), 5700 M.L.K. Jr Way, Oakland, CA, 94609, USA.
authors.forename: Jung H
authors.initials: JH
authors.lastname: Suh
authors.affiliation: Children's Hospital Oakland Research Institute (CHORI), 5700 M.L.K. Jr Way, Oakland, CA, 94609, USA.
authors.forename: Frans A
authors.initials: FA
authors.lastname: Kuypers
authors.affiliation: CFLS Data, 560 South Winchester Boulevard, San Jose, CA, 95128, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Oronsky
authors.affiliation: EpicentRx, Inc., 800 W El Camino Real, Suite 180, Mountain View, CA, 94040, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lybeck
authors.affiliation: InterWest Partners, 2710 Sand Hill Road #200, Menlo Park, CA, 94025, USA.
authors.forename: Arnold
authors.initials: A
authors.lastname: Oronsky
authors.affiliation: EpicentRx, Inc., 800 W El Camino Real, Suite 180, Mountain View, CA, 94040, USA. boronsky@epicentrx.com.
authors.forename: Bryan
authors.initials: B
authors.lastname: Oronsky
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000819:agonists / Q000096:biosynthesis; D009572:Nitrite Reductases / Q000378:metabolism; D009574:Nitro Compounds / Q000494:pharmacology*; D000072258:Tumor Hypoxia / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D001384:Azetidines; D009574:Nitro Compounds; C577469:RRx-001; D009569:Nitric Oxide; D009572:Nitrite Reductases
keywords: Deoxyhemoglobin; Nitric oxide; Nitric oxide synthase; Oncology; RRx-001