TY - JOUR
T1 - NADPH oxidase inhibition attenuates total body irradiation-induced haematopoietic genomic instability
AU - Pazhanisamy, Senthil K.
AU - Li, Hongliang
AU - Wang, Yong
AU - Batinic-Haberle, Ines
AU - Zhou, Daohong
N1 - Funding Information:
National Institutes of Health (R01-CA086688, CA102558, and AI080421); National Natural Science Foundation of China (NSFC 30828011); Winthrop W. Rockefeller Endowment for Leukaemia Research.
PY - 2011/5
Y1 - 2011/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79955373156&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79955373156&partnerID=8YFLogxK
U2 - 10.1093/mutage/ger001
DO - 10.1093/mutage/ger001
M3 - Article
C2 - 21415439
AN - SCOPUS:79955373156
SN - 0267-8357
VL - 26
SP - 431
EP - 435
JO - Mutagenesis
JF - Mutagenesis
IS - 3
ER -