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The PPARγ agonist pioglitazone crosses the blood–brain barrier and reduces tumor growth in a human xenograft model

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Abstract

Purpose

The peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear hormone receptor family, represents a target in glioma therapy due to its antineoplastic effects in vitro on human glioma cell lines. We investigate the antineoplastic effects of the PPARγ agonist pioglitazone (pio) in a human glioma xenograft model to define the minimal required dose to induce antineoplastic effects. Additionally, we assess the ability of pio to cross the blood–brain barrier by measuring brain parenchymal concentration after oral administration.

Methods

Human LN-229 cells were injected into the striatum of Balb/cJHanHsd-Prkdc-scid mice. Tumor volumes, invasion, proliferation and parenchymal pio concentrations were measured in this xenograft model after continuous intracerebral drug administration through an osmotic pump or after oral administration.

Results

Continuous intracerebral or oral administration of pio reduced tumor volumes, invasion, and proliferation in vivo. To achieve a significant antineoplastic effect, pio needed to be dosed at 240 PPM in the oral group and >1 μM when delivered intracerebrally. After oral pio administration, the drug reached >1 nM levels in brain parenchyma.

Conclusions

These data indicate that pioglitazone crosses the blood–brain barrier and has antineoplastic effects in this glioma xenograft model and may be of potential use in treatment of malignant gliomas.

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Acknowledgments

Funding for this work was provided by an ABTC2 research grant to GEL. Gary E. Landreth has received financial support for research projects on antiinflammatory actions of PPARγ agonists by GlaxoSmithKline. 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.

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Author notes

  1. Christian Grommes

    Present address: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA

Authors and Affiliations

  1. Department of Neuroscience, Case Western Reserve University, Cleveland, OH, USA

    Christian Grommes, J. Colleen Karlo, Andrew Caprariello, D’Arbra Blankenship, Anne DeChant & Gary E. Landreth

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  1. Christian Grommes
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  2. J. Colleen Karlo
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  3. Andrew Caprariello
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  4. D’Arbra Blankenship
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  5. Anne DeChant
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  6. Gary E. Landreth
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Correspondence to Christian Grommes.

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Grommes, C., Karlo, J.C., Caprariello, A. et al. The PPARγ agonist pioglitazone crosses the blood–brain barrier and reduces tumor growth in a human xenograft model. Cancer Chemother Pharmacol 71, 929–936 (2013). https://doi.org/10.1007/s00280-013-2084-2

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  • DOI: https://doi.org/10.1007/s00280-013-2084-2

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