salicylates and Ataxia-Telangiectasia

Ataxia-telangiectasia (A-T) is characterized by ataxia, genomic instability, and increased cancer incidence. Previously, iron chelator concentrations which suppressed normal cell colony formation increased A-T cell colony formation. Similarly, iron chelators preferentially increased A-T cell colony formation following peroxide exposure compared to normal cells. Last, A-T cells exhibited increased short-term sensitivity to labile iron exposure compared to normal cells, an event corrected by recombinant ATM (rATM) expression. Since chromosomal damage is important in A-T pathology and iron chelators exert beneficial effects on A-T cells, we hypothesized that iron chelators would reduce A-T cell chromosomal breaks. We treated A-T, normal, and A-T cells expressing rATM with labile iron, iron chelators, antioxidants, and t-butyl hydroperoxide, and examined chromosomal breaks and ATM activation. Additionally, the effect of ATM-deficiency on transferrin receptor (TfR) expression and TfR activity blockage in A-T and syngeneic A-T cells expressing rATM was examined. We report that (1) iron chelators and iron-free media reduce spontaneous and t-butyl hydroperoxide-induced chromosomal breaks in A-T, but not normal, or A-T cells expressing rATM; (2) labile iron exposure induces A-T cell chromosomal breaks, an event lessened with rATM expression; (3) desferal, labile iron, and copper activate ATM; (4) A-T cell TfR expression is lowered with rATM expression and (5) blocking TfR activity with anti-TfR antibodies increases A-T cell colony formation, while lowering chromosomal breaks. ATM therefore functions in iron responses and the maintenance of genomic stability following labile iron exposure.

Topics: Antibodies; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Catechin; Cell Culture Techniques; Cell Cycle Proteins; Cell Line; Chromosome Breakage; Deferoxamine; DNA-Binding Proteins; Drug Synergism; Humans; Iron; Iron Chelating Agents; Mutagens; Organometallic Compounds; Protein Serine-Threonine Kinases; Receptors, Transferrin; Recombinant Fusion Proteins; Salicylates; tert-Butylhydroperoxide; Thioctic Acid; Tumor Suppressor Proteins

Ataxia-telangiectasia is caused by mutations in the ATM gene, the protein product of which is essential for effective response to double-stranded DNA breaks. Loss of ATM function explains most aspects of the disease, but not the cerebellar neurodegeneration characteristic of the disease. Mice lacking ATM provide an excellent model of the human disorder. In addition to deficient response to DNA damage, these mice exhibit oxidative stress, which we hypothesized is the cause of cerebellar dysfunction. We show that treatment with a catalytic antioxidant corrects the neurobehavioral deficit in these mice.

Topics: Animals; Antioxidants; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Brain; Catalysis; Cell Cycle Proteins; Disease Models, Animal; DNA-Binding Proteins; Fatty Acids; Mice; Mice, Knockout; Organometallic Compounds; Oxidation-Reduction; Protein Serine-Threonine Kinases; Rotarod Performance Test; Salicylates; Tumor Suppressor Proteins