| Glitazones induce astroglioma cell death by releasing reactive oxygen species from mitochondria: modulation of cytotoxicity by nitric oxide. | |
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MedLine Citation:
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PMID: 17504946 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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José M Pérez-Ortiz; Pedro Tranque; Miguel Burgos; Cecilia F Vaquero; Juan Llopis |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2007-05-15 |
Journal Detail:
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Title: Molecular pharmacology Volume: 72 ISSN: 0026-895X ISO Abbreviation: Mol. Pharmacol. Publication Date: 2007 Aug |
Date Detail:
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Created Date: 2007-07-26 Completed Date: 2007-09-05 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 407-17 Citation Subset: IM |
Affiliation:
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Physiology Unit, Facultad de Medicina, Universidad de Castilla-La Mancha, Avenida de Almansa 14, 02006 Albacete, Spain. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Astrocytoma / drug therapy*, metabolism, pathology Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / pharmacology Cell Line, Tumor Electron Transport / drug effects Hydrogen-Ion Concentration Mitochondria / drug effects*, metabolism NADPH Oxidase / physiology NG-Nitroarginine Methyl Ester / pharmacology Nitric Oxide / physiology* Rats Reactive Oxygen Species / metabolism* Superoxides / metabolism Thiazolidinediones / pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Reactive Oxygen Species; 0/Thiazolidinediones; 10102-43-9/Nitric Oxide; 11062-77-4/Superoxides; 370-86-5/Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; 50903-99-6/NG-Nitroarginine Methyl Ester; 74772-77-3/ciglitazone; EC 1.6.3.1/NADPH Oxidase |
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