title: Epigenetic modifiers exacerbate oxidative stress in renal proximal tubule cells.
abstract: 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.
  
  
  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 H(2)O(2). 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Quintiles Hungary Ltd, Budapest, Hungary.
authors.forename: Edit
authors.initials: E
authors.lastname: Nadasi
authors.forename: Jeb S
authors.initials: JS
authors.lastname: Clark
authors.forename: Istvan
authors.initials: I
authors.lastname: Szanyi
authors.forename: Timea
authors.initials: T
authors.lastname: Varjas
authors.forename: Istvan
authors.initials: I
authors.lastname: Ember
authors.forename: Radhakrishna
authors.initials: R
authors.lastname: Baliga
authors.forename: Istvan
authors.initials: I
authors.lastname: Arany
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000077209:Decitabine; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D000964:Antimetabolites, Antineoplastic; D006877:Hydroxamic Acids; D017382:Reactive Oxygen Species; C012589:trichostatin A; D000077209:Decitabine; D001374:Azacitidine