Abstract
Despite new approaches, treatment options for malignant gliomas are still limited, calling for further development of therapeutic strategies. The peroxisome proliferator-activated receptor (PPAR)γ, a member of the nuclear hormone receptor family, represents a possible new target for neoplastic therapies. Synthetic PPARγ agonists were developed and are already in clinical use for the treatment of type II diabetes, since PPARγ plays a crucial role in lipid metabolism and regulation of insulin sensitivity. Beyond these metabolic effects, PPARγ agonists exhibit antineoplastic effects in various malignant tumor cells. Here, we investigated the antineoplastic effects of the nonthiazolidinedione tyrosine-based PPARγ 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 PPARγ agonist GW7845 may be of potential use in treatment of malignant gliomas.
Footnotes
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C.G. is supported by a grant of the Deutsche Forschungsgemeinschaft (GR 2018/1-1). U.S. and M.T.H. are supported by a grant from the German Cancer Research Council (10-1795). G.E.L. received financial support for research projects on anti-inflammatory actions of PPARγ agonists by GlaxoSmithKline. Case Western Reserve University holds a U.S. patent on the use of PPARγ agonists in inflammatory indications in the nervous system. The intellectual property and research support do not relate to the antineoplastic actions of the drugs.
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doi:10.1124/jpet.104.078972.
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ABBREVIATIONS: PPAR, peroxisome proliferator-activated receptor; GW7845, (S)-2-(1-carboxy-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]phenyl}ethylamino)benzoic acid methyl ester; GW9662, 2-chloro-5-nitro-N-phenylbenzamide; DMSO, dimethyl sulfoxide; DMEM, Dulbecco's modified Eagle's medium; PBS, phosphate-buffered saline; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PI, propidium iodide; BP, band pass; PMSF, phenylmethylsulfonyl fluoride; TBS, Tris-buffered saline; DAPI, 4,6-diamidino-2-phenylindole; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling.
- Received October 24, 2004.
- Accepted January 19, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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