Desferrioxamine treatment increases the genomic stability of Ataxia-telangiectasia cells.
Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by genomic instability, chronic oxidative damage, and increased cancer incidence. Compared to normal cells, AT cells exhibit unusual sensitivity to exogenous oxidants, including t-butyl hydroperoxide (t-BOOH). Since ferritin releases labile iron under oxidative stress (which is chronic in AT) and labile iron mediates the toxic effects of t-butyl hydroperoxide, we hypothesized that chelation of intracellular labile iron would increase the genomic stability of AT cells, with and without exogenous oxidative stress. Here we report that desferrioxamine treatment increases the plating efficiency of AT, but not normal cells, in the colony forming-efficiency assay (a method often used to measure genomic stability). Additionally, desferrioxamine increases AT, but not normal cell resistance, to t-butyl hydroperoxide in this assay. Last, AT cells exhibit increased sensitivity to the toxic effects of FeCl(2) in the colony forming-efficiency assay and fail to demonstrate a FeCl(2)-induced G(2) checkpoint response when compared to normal cells. Our data indicates that: (1) chelation of labile iron increases genomic stability in AT cells, but not normal cells; and (2) AT cells exhibit deficits in their responses to iron toxicity. While preliminary, our findings suggest that AT might be, in part, a disorder of iron metabolism and treatment of individuals with AT with desferrioxamine might have clinical efficacy.
Shackelford
Rodney E
RE
Osteopathic Medical Center, Des Moines University, Des Moines, IA 50309, USA.
Manuszak
Ryan P
RP
Johnson
Cybele D
CD
Hellrung
Daniel J
DJ
Steele
Timothy A
TA
Link
Charles J
CJ
Wang
Suming
S
D001241:Aspirin / Q000494:pharmacology; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D043171:Chromosomal Instability / Q000187:drug effects*; D003114:Colony-Forming Units Assay; D003676:Deferoxamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005293:Ferritins / Q000096:biosynthesis; D005347:Fibroblasts; D016195:G2 Phase / Q000502:physiology; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology*; D018384:Oxidative Stress; D020122:tert-Butylhydroperoxide / Q000378:metabolism / Q000633:toxicity
D007502:Iron Chelating Agents; D005293:Ferritins; D020122:tert-Butylhydroperoxide; D003676:Deferoxamine; D001241:Aspirin