Glitazones induce astroglioma cell death by releasing reactive oxygen species from mitochondria: modulation of cytotoxicity by nitric oxide.
The glitazones (or thiazolidinediones) are synthetic compounds used in type-2 diabetes, but they also have broad antiproliferative and anti-inflammatory properties still not well understood. We described previously the apoptotic effects of glitazones on astroglioma cells ( J Biol Chem 279: 8976-8985, 2004 ). At certain concentrations, we found a selective lethality on glioma cells versus astrocytes that was dependent on a rapid production of reactive oxygen species (ROS) and seemed unrelated to the receptor peroxisome proliferator activated receptor-gamma. The present study was aimed at characterizing the oxygen derivatives induced by ciglitazone, rosiglitazone, and pioglitazone in C6 glioma cells and to investigate their intracellular source. We examined the interaction of ROS with nitric oxide (NO) and its consequences for glioma cell survival. Fluorescence microscopy and flow cytometry showed that glitazones induced superoxide anion, peroxynitrite, and hydrogen peroxide, with ciglitazone being the most active. ROS production was completely prevented by uncoupling of the electron transport chain and by removal of glucose as an energy substrate, whereas it was unaffected by inhibition of NADPH-oxidase and xanthine-oxidase. Moreover, glitazones inhibited state 3 respiration in permeabilized cells, and experiments with mitochondrial inhibitors suggested that complex I was the likely target of glitazones. Therefore, these results point to the mitochondrial electron transport chain as the source of glitazone-induced ROS in C6 cells. Glitazones also depolarized mitochondria and reduced mitochondrial pH. NO synthase inhibitors revealed that superoxide anion combines with NO to yield peroxynitrite and that the latter contributes to the cytotoxicity of glitazones in astroglioma cells. Future antitumoral strategies may take advantage of these findings.
Pérez-Ortiz
José M
JM
Physiology Unit, Facultad de Medicina, Universidad de Castilla-La Mancha, Avenida de Almansa 14, 02006 Albacete, Spain.
Tranque
Pedro
P
Burgos
Miguel
M
Vaquero
Cecilia F
CF
Llopis
Juan
J
D000818:Animals; D001254:Astrocytoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D045744:Cell Line, Tumor; D004579:Electron Transport / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D019255:NADPH Oxidases / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*
D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D013481:Superoxides; D009569:Nitric Oxide; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D019255:NADPH Oxidases; C039671:ciglitazone; D019331:NG-Nitroarginine Methyl Ester