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

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.