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NEUROPHARMACOLOGY

The Nonthiazolidinedione Tyrosine-Based Peroxisome Proliferator-Activated Receptor Ligand GW7845 Induces Apoptosis and Limits Migration and Invasion of Rat and Human Glioma Cells

Department of Neurosciences, Alzheimer Research Laboratory, Case Western Reserve University, Cleveland, Ohio (C.G., G.E.L.); Department of Neurology, University of Bochum, Bochum, Germany (U.S.); and Department of Neurology, University of Muenster, Muenster, Germany (M.T.H.)

Despite new approaches, treatment options for malignant gliomas are still limited, calling for further development of therapeutic strategies. The peroxisome proliferator-activated receptor (PPAR), a member of the nuclear hormone receptor family, represents a possible new target for neoplastic therapies. Synthetic PPAR agonists were developed and are already in clinical use for the treatment of type II diabetes, since PPAR plays a crucial role in lipid metabolism and regulation of insulin sensitivity. Beyond these metabolic effects, PPAR agonists exhibit antineoplastic effects in various malignant tumor cells. Here, we investigated the antineoplastic effects of the nonthiazolidinedione tyrosine-based PPAR ligand (S)-2-(1-carboxy-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}ethylamino)benzoic acid methyl ester (GW7845) in rat and human glioma cells. GW7845 reduced cellular viability of rat C6 glioma and human glioma cells in a time-dependent manner. Analysis of GW7845-treated tumor cells revealed induction of apoptotic cell death as determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and cleaved caspase-3 activation. Furthermore, GW7845 reduced proliferation of C6 glioma cells as measured by Ki-67 immunore-activity. There was also a reduction of migration and invasion, assessed by Boyden chamber and spheroid experiments. Together, these data indicate that the PPAR agonist GW7845 may be of potential use in treatment of malignant gliomas.

Address correspondence to: Dr. 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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