TY - JOUR T1 - Epigenetic Modifiers Exert Renal Toxicity through Induction of p66shc JF - Anticancer Research JO - Anticancer Res SP - 3267 LP - 3271 VL - 31 IS - 10 AU - ISTVAN ARANY AU - JEB S. CLARK AU - ISTVAN EMBER AU - LUIS A. JUNCOS Y1 - 2011/10/01 UR - http://ar.iiarjournals.org/content/31/10/3267.abstract N2 - Background/Aims: Trichostatin A (TSA) and 5-azacytidine (5AZA) induce reactive oxygen species (ROS)-mediated injury in renal proximal tubule cells. Since TSA and 5AZA are activators of p66shc, we questioned whether p66shc may mediate renal toxicity of TSA- and 5AZA. Materials and Methods: Renal proximal tubule cells were treated with either TSA or 5AZA for 24 hours followed by treatment with 200 μM H2O2. Expression of p66shc and activity of its promoter, as well as its mitochondrial and cytochrome c binding were determined. Impact of knockdown of p66shc and mutation of its cytochrome c-binding site on ROS production and cell injury was studied. Results: TSA, and 5AZA increased expression of p66shc through induction of its promoter and also increased its mitochondrial/cytochrome c binding. Knockdown or mutation of the cytochrome c binding site of p66shc attenuated ROS production and cell injury. Conclusion: Therapeutic means that interfere with induction of p66shc may ameliorate renal toxicity of those epigenetic modifiers. ER -