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Inhibition of in Vivo Glioma Growth and Invasion by Peroxisome Proliferator-Activated Receptor Agonist Treatment

Department of Neurosciences, Alzheimer Research Laboratory (C.G., G.E.L.) and Department of Neurology (C.G.), Case Western Reserve University, Cleveland, Ohio; Department of Neurology, University of Muenster, Muenster, Germany (M.T.H.); Department of Neurology, University of Bonn Medical Center, Bonn, Germany (M.S., M.B.); Department of Neurology, University of Bochum, Bochum, Germany (U.S.); Department of Anesthesiology, University of Illinois, Chicago, Illinois (D.L.F.); and Department of Neurology, University of Cologne, Cologne, Germany (A.H.J.)

The peroxisome proliferator-activated receptor (PPAR), a member of the nuclear hormone receptor family, represents a possible new target in glioma therapy. Because PPAR 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, PPAR agonists exhibit antineoplastic effects. In this study, we investigated the antineoplastic effects of the PPAR agonist pioglitazone in glioma cells. Pioglitazone reduced cellular viability of rat, human, and PPAR-overexpressing glioma cells in vitro in a time- and concentration-dependent manner. No antineoplastic effects were induced by pioglitazone in glioma cells overexpressing a PPAR 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.

Address correspondence to: Michael T. Heneka, Department of Neurology, University of Muenster, Albert-Schweitzer-Str. 33, 48149 Muenster, Germany. E-mail: heneka{at}uni-muenster.de

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