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Received for publication January 27, 2006.
Revised July 12, 2006.
Accepted for publication July 12, 2006.
agonist treatment
The peroxisome proliferator-activated receptor gamma (PPAR
), a member of the nuclear hormone receptor family, represents a possible new target in glioma therapy. Since 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. Here, 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, 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 MMP9 levels in vivo indicate pio-mediated reduction of invasion. Together, these data indicate that pioglitazone may be of potential use in treatment of malignant gliomas.
Key words:
Orphan, PPARs, Mechanisms of cell killing/apoptosis, Pharmacokinetics, metabolism and activation
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