title: Ligands for PPARgamma and RAR cause induction of growth inhibition and apoptosis in human glioblastomas.
abstract: High-grade gliomas are characterized by a rapid proliferation rate, invasiveness and angiogenesis. Our previous data indicated that the combination of ligands for peroxisome proliferator-activated receptor gamma (PPARgamma) and retinoic acid receptor (RAR) induces apoptosis of breast cancer cells in vitro and in a murine model. In this study, we have shown that 11 glioblastoma cell lines and nine fresh glioblastoma tissue samples from patients expressed high-levels of PPARgamma. In contrast, glia from nine healthy human brains expressed very low levels of PPARgamma. No mutations or polymorphisms of the PPARgamma gene were observed in these cell lines. The effect of the PPARgamma ligand Pioglitazone (PGZ) either in the absence or in the presence of a RAR ligand [all-trans retinoic acid (ATRA)] on the proliferation and apoptosis of glioblastoma cells was examined using two glioblastoma cell lines (N39 and DBTRG05MG). PGZ and/or ATRA inhibited significantly the proliferation of both cell lines. Flow cytometry analysis showed that G1 cell cycle arrest was induced by these ligands. In addition, apoptosis occurred in both cell lines treated with either PGZ or ATRA, which was associated with a downregulation of bcl-2 and an upregulation of bax proteins. An enhanced effect was observed when PGZ and ATRA were combined. Furthermore, treatment of fresh glioblastoma tissue from patients with PGZ, either alone or in combination with ATRA, induced a significant level of tumor cell apoptosis together with a downregulation of bcl-2 protein level as compared with untreated control brain tissue. Taken together, our data demonstrated that PGZ, either alone or in combination with ATRA, induced apoptosis and inhibited proliferation of glioblastoma cells, and more interestingly, induced apoptosis of fresh glioblastoma cells from patients. Therefore, we conclude that these ligands may possess adjuvant therapeutic potential for patients with glioblastoma.
authors.affiliation: Division of Oncology/Hematology, School of Medicine (Charité), Humboldt University, Berlin, Germany.
authors.forename: Chuanbing
authors.initials: C
authors.lastname: Zang
authors.forename: Marlies
authors.initials: M
authors.lastname: Wächter
authors.forename: Hongyu
authors.initials: H
authors.lastname: Liu
authors.forename: Maximilian G
authors.initials: MG
authors.lastname: Posch
authors.forename: Martin H
authors.initials: MH
authors.lastname: Fenner
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Kurt
authors.initials: K
authors.lastname: Possinger
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
authors.forename: Elena
authors.initials: E
authors.lastname: Elstner
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004338:Drug Combinations; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008024:Ligands; D000077205:Pioglitazone; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; D004268:DNA-Binding Proteins; D004338:Drug Combinations; D008024:Ligands; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D045162:Thiazolidinediones; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D014212:Tretinoin; D000077205:Pioglitazone