Epigenetic modifiers exacerbate oxidative stress in renal proximal tubule cells.
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.
Nadasi
Edit
E
Quintiles Hungary Ltd, Budapest, Hungary.
Clark
Jeb S
JS
Szanyi
Istvan
I
Varjas
Timea
T
Ember
Istvan
I
Baliga
Radhakrishna
R
Arany
Istvan
I
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*
D000935:Antifungal Agents; D000964:Antimetabolites, Antineoplastic; D006877:Hydroxamic Acids; D017382:Reactive Oxygen Species; C012589:trichostatin A; D000077209:Decitabine; D001374:Azacitidine