Iron chelators increase the genomic stability of ataxia-telangeictasia cells.

Proc Amer Assoc Cancer Res, Volume 45, 2004 3819 Ataxia-telangeictasia (AT) is an autosomal recessive disorder characterized by immune dysfunction, 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. 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. At first, we found that the ferrous iron chelator desferrioxamine was shown to increase resistance to exogenous oxidative stress of AT, but not normal cells, in the colony forming-efficiency assay. This data suggested that iron metabolism is dysregulated in AT. Since desferrioxamine alters gene expression, as well as chelates iron, we tested the effect of apoferritinn and the iron chelating flavonoid quercetin on AT cell genomic stability. The data shown that apoferritin and quercetin increase the genomic stability of AT cells. To further analyze the role of labile iron in AT, we measured labile iron in the sera of AT knockout mice and found significantly elevated iron levels compared to syngeniec wild type mice. Our data supports a role for increased labile iron acting as a Fenton catalyst in AT, thus contributing to the chronic oxidative stress seen in this disease. Our data further suggests that iron chelators as a class might promote genomic stability in AT cells.