title: Inactivation of NADPH oxidases NOX4 and NOX5 protects human primary fibroblasts from ionizing radiation-induced DNA damage.
abstract: Human exposure to ionizing radiation from medical procedures has increased sharply in the last three decades. Recent epidemiological studies suggest a direct relationship between exposure to ionizing radiation and health problems, including cancer incidence. Therefore, minimizing the impact of radiation exposure in patients has become a priority in the development of future clinical practices. Crucial players in radiation-induced DNA damage include reactive oxygen species (ROS), but the sources of these have remained elusive. To the best of our knowledge, we show here for the first time that two members of the ROS-generating NADPH oxidase family (NOXs), NOX4 and NOX5, are involved in radiation-induced DNA damage. Depleting these two NOXs in human primary fibroblasts resulted in reduced levels of DNA damage as measured by levels of radiation-induced foci, a marker of DNA double-strand breaks (DSBs) and the comet assay coupled with increased cell survival. NOX involvement was substantiated with fulvene-5, a NOXs-specific inhibitor. Moreover, fulvene-5 mitigated radiation-induced DNA damage in human peripheral blood mononuclear cells ex vivo. Our results provide evidence that the inactivation of NOXs protects cells from radiation-induced DNA damage and cell death. These findings suggest that NOXs inhibition may be considered as a future pharmacological target to help minimize the negative effects of radiation exposure for millions of patients each year.
authors.affiliation: a Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Urbain
authors.initials: U
authors.lastname: Weyemi
authors.forename: Christophe E
authors.initials: CE
authors.lastname: Redon
authors.forename: Towqir
authors.initials: T
authors.lastname: Aziz
authors.forename: Rohini
authors.initials: R
authors.lastname: Choudhuri
authors.forename: Daisuke
authors.initials: D
authors.lastname: Maeda
authors.forename: Palak R
authors.initials: PR
authors.lastname: Parekh
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Bonner
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
authors.forename: William M
authors.initials: WM
authors.lastname: Bonner
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D003517:Cyclopentanes / Q000008:administration & dosage*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage / Q000235:genetics* / Q000528:radiation effects; D005347:Fibroblasts / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D000074663:NADPH Oxidase 4; D000074664:NADPH Oxidase 5; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics*; D061251:Primary Cell Culture; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D003517:Cyclopentanes; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; C543098:fulvene-5; D000074663:NADPH Oxidase 4; D000074664:NADPH Oxidase 5; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C431571:NOX5 protein, human