Pioglitazone as a Treatment Option for Ataxia-Telangiectasia

Abstract

Abstract Introduction/Objective The ataxia-telangiectasia mutated (ATM) gene product regulates cell cycle checkpoints, the cellular redox state, and DNA break repair. ATM loss causes the rare disorder ataxia-telangiectasia (A-T), characterized by progressive ataxia, telangiectasias, immune dysfunction, and an elevated cancer risk. The clinical course of A-T is relentless, causing death by the early twenties. Methods/Case Report A-T cells show extreme sensitivity to oxidants and ionizing radiation, impaired glutathione (GSH) synthesis, genomic instability, poor cell cycle checkpoint initiation, and increased reactive oxygen species. A-T cells also show unusual iron responses, with iron chelators increasing A-T cell growth, oxidant exposure resistance, and genomic stability, while labile iron exerts toxic effects not seen in ATM wild-type cells. Since GSH is dysregulated in A-T cells and much of the cellular iron is bound up in iron-sulfur clusters, we examined the cellular sulfur pool in A-T cells with and without an ATM expression vector, and in ATM wild-types cells. Free hydrogen sulfide and protein- bound sulfide levels were unchanged with ATM expression. However, iron-sulfur clusters (the acid-labile sulfur faction) were low in the A-T cells and dramatically increased with ATM expression. ATM expression also increased the expression of NFS1, NFU1, and several mitochondrial complex I iron-sulfur proteins. As NFS1 and NFU1 play central roles in the synthesis of iron-sulfur clusters, and ATM expression increases these clusters, our data reveals a role for ATM in iron metabolism. Interestingly, the type II diabetes drug pioglitazone increased the acid-labile sulfur and protein bound sulfur factions in both cell types. It also increased the A-T cell reduced GSH, cell viability following oxidative stress, and decreased oxidative stress-induced double-stranded DNA break formation. Results (if a Case Study enter NA) Our finding that pioglitazone increased both cellular acid-labile and protein-bound sulfur fractions, indicates that these sulfur pools may be a therapeutic target for some type II diabetes drugs. Our data also indicates that pioglitazone may have value in treating A-T Conclusion We propose that pioglitazone could be a promising A-T treatment drug. More clinical research and trials are needed to determine the potential advantages and side effects of using pioglitazone in A-T.