title: RRx-001, a novel clinical-stage chemosensitizer, radiosensitizer, and immunosensitizer, inhibits glucose 6-phosphate dehydrogenase in human tumor cells.
abstract: The anti-proliferative effects of RRx-001, a novel RONS-mediated immuno-epigenetic and vascular normalizing anticancer agent in Phase 2 clinical trials, are not explainable via a single mechanism. Previous research suggested an association between G6PD inhibition and RRx-001 anticancer activity. The results in this study confirm and extend previous observations that RRx-001 exerts its anti-proliferative effect, at least partially, through interference with glucose 6 phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway, responsible for maintaining adequate levels of the major cellular reductant, NADPH. RRx-001 affects glucose and G6PD enzyme activity in three different cancer cell lines namely Hep G2, CACO-2, and HT-29. We observed that in all cancer cell lines tested, RRx-001 induced G6PD inhibition in a concentration dependent fashion. Inhibition of G6PD activity associated with a reduction in ribonucleotide synthesis, glutathione reduction and cell proliferation may represent an important mechanism by which RRx-001 exerts its anticancer effects.
authors.affiliation: EpicentRx Inc., 800 W. El Camino Real, Suite 180, Mountain View, CA 94040, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Oronsky
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: Moores Cancer Center, University of California, 3855 Health Sciences Dr., La Jolla, CA 92093, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Reid
authors.affiliation: InterWest Partners, 2710 Sand Hill Rd. #200, Menlo Park, CA 94025, USA.
authors.forename: Arnold
authors.initials: A
authors.lastname: Oronsky
authors.affiliation: Walter Reed National Military Medical Center, 8901 Wisconsin Ave., Bethesda, MD 20889, USA.
authors.forename: Corey
authors.initials: C
authors.lastname: Carter
authors.affiliation: CFLS Data, 800 W. El Camino Real, Suite 180, Mountain View, CA 94040, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Oronsky
authors.affiliation: Department of Bioengineering, University of California at San Diego (UCSD), 9500 Gilman Dr., La Jolla, CA 92093, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Cabrales
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology*; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects*; D017322:Clinical Trials, Phase II as Topic; D005947:Glucose / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D009249:NADP / Q000378:metabolism; D009574:Nitro Compounds / Q000494:pharmacology*; D010427:Pentose Phosphate Pathway / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D001384:Azetidines; D009574:Nitro Compounds; C577469:RRx-001; D009249:NADP; D005954:Glucosephosphate Dehydrogenase; D005947:Glucose