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Molecular Pharmacology

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Research ArticleArticle

Glitazones Induce Astroglioma Cell Death by Releasing Reactive Oxygen Species from Mitochondria: Modulation of Cytotoxicity by Nitric Oxide

José M. Pérez-Ortiz, Pedro Tranque, Miguel Burgos, Cecilia F. Vaquero and Juan Llopis
Molecular Pharmacology August 2007, 72 (2) 407-417; DOI: https://doi.org/10.1124/mol.106.032458
José M. Pérez-Ortiz
Physiology Unit, Facultad de Medicina, and Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, Albacete, Spain
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Pedro Tranque
Physiology Unit, Facultad de Medicina, and Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, Albacete, Spain
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Miguel Burgos
Physiology Unit, Facultad de Medicina, and Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, Albacete, Spain
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Cecilia F. Vaquero
Physiology Unit, Facultad de Medicina, and Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, Albacete, Spain
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Juan Llopis
Physiology Unit, Facultad de Medicina, and Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, Albacete, Spain
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Abstract

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 Chem279:8976-8985, 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-γ. 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.

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Molecular Pharmacology: 72 (2)
Molecular Pharmacology
Vol. 72, Issue 2
1 Aug 2007
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Research ArticleArticle

Glitazones Induce Astroglioma Cell Death by Releasing Reactive Oxygen Species from Mitochondria: Modulation of Cytotoxicity by Nitric Oxide

José M. Pérez-Ortiz, Pedro Tranque, Miguel Burgos, Cecilia F. Vaquero and Juan Llopis
Molecular Pharmacology August 1, 2007, 72 (2) 407-417; DOI: https://doi.org/10.1124/mol.106.032458

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Research ArticleArticle

Glitazones Induce Astroglioma Cell Death by Releasing Reactive Oxygen Species from Mitochondria: Modulation of Cytotoxicity by Nitric Oxide

José M. Pérez-Ortiz, Pedro Tranque, Miguel Burgos, Cecilia F. Vaquero and Juan Llopis
Molecular Pharmacology August 1, 2007, 72 (2) 407-417; DOI: https://doi.org/10.1124/mol.106.032458
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