The PPARγ agonist pioglitazone crosses the blood-brain barrier and reduces tumor growth in a human xenograft model.
OBJECTIVE
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.
Department of Neuroscience, Case Western Reserve University, Cleveland, OH, USA. grommesc@mskcc.org
Christian
C
Grommes
J Colleen
JC
Karlo
Andrew
A
Caprariello
D'Arbra
D
Blankenship
Anne
A
Dechant
Gary E
GE
Landreth
D000818:Animals; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000493:pharmacokinetics* / Q000627:therapeutic use; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D047495:PPAR gamma; D045162:Thiazolidinediones; D000077205:Pioglitazone