[en] The peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear hormone receptor family, represents a possible new target in glioma therapy. Because PPARgamma plays a crucial role in regulation of insulin sensitivity, synthetic agonists are already in clinical use for type II diabetes treatment. Beyond these metabolic effects, PPARgamma agonists exhibit antineoplastic effects. In this study, we investigated the antineoplastic effects of the PPARgamma agonist pioglitazone in glioma cells. Pioglitazone reduced cellular viability of rat, human, and PPARgamma-overexpressing glioma cells in vitro in a time- and concentration-dependent manner. No antineoplastic effects were induced by pioglitazone in glioma cells overexpressing a PPARgamma mutant. Furthermore, proliferation was reduced by pioglitazone, as measured by Ki-67 immunoreactivity, in vitro. Continuous intracerebral infusion of pioglitazone into gliomas induced by intrastriatal injection of C6 cells reduced tumor volumes by 83%. Oral administration of pioglitazone reduced tumor volumes by 76.9%. Subsequent brain tissue analysis revealed induction of apoptotic cell death. Ki-67 expression and BrdU incorporation revealed a reduction of proliferation in vivo. Reduced invasion of C6 cells and lower matrix metalloproteinase 9 levels in vivo indicate pioglitazone-mediated reduction of invasion. Together, these data indicate that pioglitazone may be of potential use in treatment of malignant gliomas.
Disciplines :
Neurologie
Auteur, co-auteur :
Grommes, Christian; Department of Neurosciences, Alzheimer Research Laboratory, Case Western Reserve University, Cleveland, Ohio, USA
Landreth, Gary E; Department of Neurosciences, Alzheimer Research Laboratory, Case Western Reserve University, Cleveland, OH, United States
Sastre, Magdalena; Department of Neurology, University of Bonn Medical Center, Bonn, Germany
Beck, Martina; Department of Neurology, University of Bonn Medical Center, Bonn, Germany
Feinstein, Douglas L; Department of Anesthesiology, University of Illinois, Chicago, IL, United States
Jacobs, Andreas H; Department of Neurology, University of Cologne, Cologne, Germany
Schlegel, Uwe; Department of Neurology, University of Bochum, Bochum, Germany
HENEKA, Michael ; Department of Neurology, University of Muenster, Muenster, Germany ; Department of Neurology, University of Muenster, 48149 Muenster, Germany
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
Inhibition of in vivo glioma growth and invasion by peroxisome proliferator-activated receptor gamma agonist treatment.
Date de publication/diffusion :
novembre 2006
Titre du périodique :
Molecular Pharmacology
ISSN :
0026-895X
eISSN :
1521-0111
Maison d'édition :
American Society for Pharmacology & Experimental Therapeutics (ASPET), Etats-Unis
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