title: Borane-protected phosphines are redox-active radioprotective agents for endothelial cells.
abstract: Exposure to radiation can damage endothelial cells in the irradiated area via the production of reactive oxygen species. We synthesized phosphine-borane complexes that reduce disulfide bonds and had previously been shown to interfere with redox-mediated signaling of cell death. We hypothesized that this class of drugs could interfere with the downstream effects of oxidative stress after irradiation and rescue endothelial cells from radiation damage. Cultured bovine aortic endothelial cells were plated for clonogenic assay prior to exposure to varying doses of irradiation from a (137)Cs irradiator and treated with various concentrations of bis(3-propionic acid methyl ester)phenylphosphine borane complex (PB1) at different time points. The clone-forming ability of the irradiated cells was assessed seven days after irradiation. We compared the radioprotective effects of PB1 with the aminothiol radioprotectant WR1065 and known superoxide scavengers. PB1 significantly protected bovine aortic endothelial cells from radiation damage, particularly when treated both before and after radiation. The radioprotection with 1 µM PB1 corresponded to a dose-reduction factor of 1.24. Radioprotection by PB1 was comparable to the aminothiol WR1065, but was significantly less toxic and required much lower concentrations of drug (1 µM vs. 4 mM, respectively). Superoxide scavengers were not radioprotective in this paradigm, indicating the mechanisms for both loss of clonogenicity and PB1 radioprotection are independent of superoxide signaling. These data demonstrate that PB1 is an effective redox-active radioprotectant for endothelial cells in vitro, and is radioprotective at a concentration approximately 4 orders of magnitude lower than the aminothiol WR1065 with less toxicity.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Crowe
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States; Cytodefense, Madison, WI, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lieven
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States.
authors.forename: Alex F
authors.initials: AF
authors.lastname: Thompson
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States.
authors.forename: Nader
authors.initials: N
authors.lastname: Sheibani
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States; Cytodefense, Madison, WI, United States; Department of Ophthalmology, McGill University, Montreal, QC, Canada.
authors.forename: Leonard A
authors.initials: LA
authors.lastname: Levin
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D001880:Boranes / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D002999:Clone Cells; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D005720:Gamma Rays / Q000009:adverse effects*; D006801:Humans; D008624:Mercaptoethylamines / Q000494:pharmacology; D008665:Metalloporphyrins / Q000494:pharmacology; D010084:Oxidation-Reduction; D010720:Phosphines / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000494:pharmacology; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001880:Boranes; D008624:Mercaptoethylamines; D008665:Metalloporphyrins; C502230:Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl)porphyrin; D010720:Phosphines; D011837:Radiation-Protective Agents; C515673:bis(3-propionic acid methyl ester)phenylphosphine borane complex; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D013481:Superoxides; D011092:Polyethylene Glycols; D013482:Superoxide Dismutase; C063471:polyethylene glycol-superoxide dismutase
keywords: Disulfide reduction; Endothelial cells; Phosphine–borane complexes; Radiation; Radioprotection