Inhibition of in vivo glioma growth and invasion by peroxisome proliferator-activated receptor gamma agonist treatment.
The peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear hormone receptor family, represents a possible new target in glioma therapy. Because PPARgamma 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, PPARgamma agonists exhibit antineoplastic effects. In this study, we investigated the antineoplastic effects of the PPARgamma agonist pioglitazone in glioma cells. Pioglitazone reduced cellular viability of rat, human, and PPARgamma-overexpressing glioma cells in vitro in a time- and concentration-dependent manner. No antineoplastic effects were induced by pioglitazone in glioma cells overexpressing a PPARgamma 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.
Grommes
Christian
C
Department of Neurosciences, Alzheimer Research Laboratory, Case Western Reserve University, Cleveland, Ohio, USA.
Landreth
Gary E
GE
Sastre
Magdalena
M
Beck
Martina
M
Feinstein
Douglas L
DL
Jacobs
Andreas H
AH
Schlegel
Uwe
U
Heneka
Michael T
MT
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D001973:Bromodeoxyuridine; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D019394:Ki-67 Antigen / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009374:Neoplasms, Experimental; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D016896:Treatment Outcome; D047368:Tumor Burden / Q000276:immunology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D004273:DNA, Neoplasm; D019394:Ki-67 Antigen; D047495:PPAR gamma; D045162:Thiazolidinediones; D051028:bcl-2-Associated X Protein; D053148:Caspase 3; D020780:Matrix Metalloproteinase 9; D001973:Bromodeoxyuridine; D000077205:Pioglitazone