PPARgamma and RXRgamma ligands act synergistically as potent antineoplastic agents in vitro and in vivo glioma models.
Glioblastoma represent the most common primary brain tumor in adults and are currently considered incurable. We investigated antiproliferative and anti-invasive mechanisms of 6-OH-11-O-hydroxyfenantrene (IIF), a retinoid X receptor ligand, and pioglitazone (PGZ), a peroxisome proliferator-activated receptor gamma activator, in three different glioblastoma cell lines. A dose-dependent reduction of tumor invasion and strong decrease of matrix metalloproteinases 2 and 9 expression was observed, especially when a combination therapy of IIF and PGZ was administered. Combined treatment also markedly reduced proliferation and induced apoptosis in all glioma cell lines tested. This was in particular accompanied by decrease of antiapoptotic proteins Bcl2 and p53, while simultaneously pro-apoptotic cytochrome c, cleaved caspase 3, Bax and Bad levels increased. These in vitro findings were further substantiated in a murine glioma model in vivo, where oral administration of PGZ and IIF resulted in significantly reduced tumor volume and proliferation. Of note, treatment with nuclear receptor ligands was not only effective when the treatment was initiated shortly after the intraparenchymal seeding of the glioma cells, but even when initiated in the last third of the observation period. Collectively, our results demonstrate the effectiveness of a combined treatment of ligands of proliferator-activated receptor and retinoid X receptor against glioblastoma.
Papi
Alessio
A
Department of Experimental Biology, University of Bologna, Bologna, Italy.
Tatenhorst
Lars
L
Terwel
Dick
D
Hermes
Michael
M
Kummer
Markus P
MP
Orlandi
Marina
M
Heneka
Michael T
MT
D000704:Analysis of Variance; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D001973:Bromodeoxyuridine / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D008024:Ligands; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D047495:PPAR gamma / Q000378:metabolism / Q000627:therapeutic use*; D000077205:Pioglitazone; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D047491:Retinoid X Receptor gamma / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D045162:Thiazolidinediones / Q000627:therapeutic use; D014162:Transfection / Q000379:methods; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014410:Tumor Stem Cell Assay / Q000379:methods; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D017304:Annexin A5; D000970:Antineoplastic Agents; C494826:BAX protein, human; C475805:IIF compound; D008024:Ligands; D047495:PPAR gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D047491:Retinoid X Receptor gamma; D013778:Tetrazolium Salts; D013844:Thiazoles; D045162:Thiazolidinediones; D051028:bcl-2-Associated X Protein; D014212:Tretinoin; D045304:Cytochromes c; D053148:Caspase 3; D020782:Matrix Metalloproteinases; C022616:thiazolyl blue; D001973:Bromodeoxyuridine; D000077205:Pioglitazone