title: Oncostatic activity of a thiazolidinedione derivative on human androgen-dependent prostate cancer cells.
abstract: Thiazolidinedione derivatives with potent antiarthritic activity, such as CGP 52608, have been suggested to exert their biological effects through the activation of the orphan nuclear receptor RORalpha. Since response elements for this receptor are present in the promoter region of cell cycle-related genes (i.e., p21(WAF1/CIP1) and cyclin A), we reasoned that CGP 52608 might affect cell proliferation, cell cycle progression and the expression of cell cycle-related genes. This hypothesis has been verified in the human androgen-dependent prostate cancer cell line LNCaP. We found that the treatment of LNCaP cells with CGP 52608 brings about a significant and dose-dependent decrease of cell proliferation. Thiazolidinedione affected cell cycle distribution, inducing an accumulation of the cells in the G0/G1 phase and a decrease in the S phase. This effect was accompanied by an increased expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and a decreased expression of cyclin A. These data indicate that, in human androgen-dependent LNCaP prostate cancer cells, the thiazolidinedione derivative CGP 52608 exerts a strong cytostatic activity, by reducing cell proliferation and by affecting cell cycle distribution through the modulation of the expression of cell cycle-related genes. These biological actions of CGP 52608 might be mediated by the activation of the orphan nuclear RORalpha receptor, which is expressed in LNCaP cells.
authors.affiliation: Center for Endocrinological Oncology, Department of Endocrinology, University of Milano, Via Balzaretti 9, 20133 Milan, Italy.
authors.forename: R M
authors.initials: RM
authors.lastname: Moretti
authors.forename: M
authors.initials: M
authors.lastname: Montagnani Marelli
authors.forename: M
authors.initials: M
authors.lastname: Motta
authors.forename: P
authors.initials: P
authors.lastname: Limonta
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000473:pathology; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013882:Thiosemicarbazones / Q000494:pharmacology* / Q000627:therapeutic use; D015534:Trans-Activators / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D000728:Androgens; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539738:RORA protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D013882:Thiosemicarbazones; D015534:Trans-Activators; C092451:CGP 52608