NADPH oxidase inhibition attenuates total body irradiation-induced haematopoietic genomic instability.

Published

Journal Article

Ionising radiation (IR) is a known carcinogen and poses a significant risk to the haematopoietic system for the development of leukaemia in part by induction of genomic instability. Induction of chronic oxidative stress has been assumed to play an important role in mediating the effect of IR on the haematopoietic system. However, there was no direct evidence to support this hypothesis prior to our studies. In our recent studies, we showed that exposure of mice to total body irradiation (TBI) induces persistent oxidative stress selectively in haematopoietic stem cells (HSCs) at least in part via up-regulation of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 4. Now, we found that post-TBI treatment with diphenylene iodonium (DPI), a pan NOX inhibitor, not only significantly reduces TBI-induced increases in reactive oxygen species (ROS) production, oxidative DNA damage and DNA double-strand breaks in HSCs but also dramatically decreases the number of cells with unstable chromosomal aberrations in the clonal progeny of irradiated HSCs. The effects of DPI are comparable to Mn (III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin, a superoxide dismutase mimetic and a potent antioxidant. These findings demonstrate that increased production of ROS by NOX in HSCs mediates the induction of haematopoietic genomic instability by IR and that NOX may represent a novel molecular target to inhibit TBI-induced genomic instability.

Full Text

Duke Authors

Cited Authors

  • Pazhanisamy, SK; Li, H; Wang, Y; Batinic-Haberle, I; Zhou, D

Published Date

  • May 2011

Published In

Volume / Issue

  • 26 / 3

Start / End Page

  • 431 - 435

PubMed ID

  • 21415439

Pubmed Central ID

  • 21415439

Electronic International Standard Serial Number (EISSN)

  • 1464-3804

Digital Object Identifier (DOI)

  • 10.1093/mutage/ger001

Language

  • eng

Conference Location

  • England