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Molecular Pharmacology

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Research ArticleArticle

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

Christian Grommes, Gary E. Landreth, Magdalena Sastre, Martina Beck, Douglas L. Feinstein, Andreas H. Jacobs, Uwe Schlegel and Michael T. Heneka
Molecular Pharmacology November 2006, 70 (5) 1524-1533; DOI: https://doi.org/10.1124/mol.106.022194
Christian Grommes
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Gary E. Landreth
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Magdalena Sastre
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Martina Beck
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Douglas L. Feinstein
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Andreas H. Jacobs
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Uwe Schlegel
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Michael T. Heneka
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Abstract

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

Footnotes

  • C.G. was supported by a grant from the German research council (GR 2018/1-1); U.S. and M.T.H. were supported by a grant from the German Cancer research council (10-1795). The work was also supported by the Blanchette Hoker Rockefeller foundation.

  • Conflict of interest statment: G.E.L. has received financial support for research projects on anti-inflammatory actions of PPARγ agonists by Glaxo-SmithKline. Case Western Reserve University holds a US 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.

  • ABBREVIATIONS: PPAR, peroxisome proliferator-activated receptor; GW9662, 2-chloro-5-nitrobenzanilide; pio, pioglitazone; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; MMP9, matrix metalloproteinase 9; DMSO, dimethyl sulfoxide; DMEM, Dulbecco's modified Eagle's medium; PBS, phosphate-buffered saline; MTT, [4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; HE, hematoxylin-eosin; TBS, Tris-buffered saline; DAPI, 4,6-diamidino-2-phenylindole; BrdU, 5-bromodeoxyuridine; PBS, phosphate-buffered saline.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received January 3, 2006.
    • Accepted July 12, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (5)
Molecular Pharmacology
Vol. 70, Issue 5
1 Nov 2006
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Research ArticleArticle

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

Christian Grommes, Gary E. Landreth, Magdalena Sastre, Martina Beck, Douglas L. Feinstein, Andreas H. Jacobs, Uwe Schlegel and Michael T. Heneka
Molecular Pharmacology November 1, 2006, 70 (5) 1524-1533; DOI: https://doi.org/10.1124/mol.106.022194

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Research ArticleArticle

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

Christian Grommes, Gary E. Landreth, Magdalena Sastre, Martina Beck, Douglas L. Feinstein, Andreas H. Jacobs, Uwe Schlegel and Michael T. Heneka
Molecular Pharmacology November 1, 2006, 70 (5) 1524-1533; DOI: https://doi.org/10.1124/mol.106.022194
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