TY - JOUR T1 - Epigenetic Modifiers Exacerbate Oxidative Stress in Renal Proximal Tubule Cells JF - Anticancer Research JO - Anticancer Res SP - 2295 LP - 2299 VL - 29 IS - 6 AU - EDIT NADASI AU - JEB S. CLARK AU - ISTVAN SZANYI AU - TIMEA VARJAS AU - ISTVAN EMBER AU - RADHAKRISHNA BALIGA AU - ISTVAN ARANY Y1 - 2009/06/01 UR - http://ar.iiarjournals.org/content/29/6/2295.abstract N2 - Background: Increased production of reactive oxygen species (ROS) by anticancer drugs has been described in patients with various malignancies, which might attribute to their nephrotoxicity. Materials and Methods: The effects of two epigenetic modifiers - trichostatin A (TSA) and 5-aza-deoxycytidine (5AZA) - on ROS production and cell injury alone or in combination with mild oxidative stress were studied in mouse renal proximal tubule cells. Results: Both agents increased mitochondrial ROS production and consequent lactate dehydrogenase (LDH) release either alone or in combination with a low dose of H2O2. The antioxidant N-acetyl-cysteine (NAC) abolished LDH release. It was also found that CREB-mediated transcription, vital for survival of proximal tubule cells, is attenuated by these anticancer agents. Conclusion: The ROS-inducing activity of TSAI and 5AZA might explain the in vivo nephrotoxicity of epigenetic modifiers. The mechanisms that are responsible for this injury could involve attenuation of pro-survival signaling and/or activation of death signaling pathway(s) associated with mitochondrial ROS release. ER -