Pharmacological Exploitation of the Peroxisome Proliferator-Activated Receptor γ Agonist Ciglitazone To Develop a Novel Class of Androgen Receptor-Ablative Agents
- 13 March 2008
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 51 (7), 2100-2107
- https://doi.org/10.1021/jm701212m
Abstract
On the basis of our finding that the peroxisome proliferator-activated receptor γ (PPARγ) agonist ciglitazone at high doses was able to mediate PPARγ-independent transcriptional repression of androgen receptor (AR) in a tumor cell-specific manner, we used Δ2CG, a PPARγ-inactive analogue of ciglitazone, to conduct lead optimization to develop a novel class of AR-ablative agents. Structure–activity analysis indicates a high degree of flexibility in realigning Δ2CG’s structural moieties without compromising potency in AR repression, as evidenced by the higher AR-ablative activity of the permuted isomer 9 [(Z)-5-(4-hydroxybenzylidene)-3-(1-methylcyclohexylmethyl)thiazolidine-2,4-dione]. Further modificiations of 9 gave rise to 12 [(Z)-5-(4-hydroxy-3-trifluoromethylbenzylidene)-3-(1-methylcyclohexylmethyl)thiazolidine-2,4-dione], which completely inhibited AR expression in LNCaP cells at low micromolar concentrations. This AR down-regulation led to growth inhibition in LNCaP cells through apoptosis induction. Moreover, the role of AR repression in the antiproliferative effect of compound 12 was validated by the differential inhibition of cell viability between androgen-responsive and androgen-nonresponsive cells.Keywords
This publication has 33 references indexed in Scilit:
- Thiazolidinediones Modulate the Expression of β-Catenin and Other Cell-Cycle Regulatory Proteins by Targeting the F-Box Proteins of Skp1-Cul1-F-box Protein E3 Ubiquitin Ligase Independently of Peroxisome Proliferator-Activated Receptor γMolecular Pharmacology, 2007
- Peroxisome Proliferator-Activated Receptor γ–Independent Suppression of Androgen Receptor Expression by Troglitazone Mechanism and Pharmacologic ExploitationCancer Research, 2007
- Letter to the Editor: Androgens and Prostate Cancer: Are the Descriptors Valid?Cancer Biology & Therapy, 2005
- Androgen Receptor Regulation by Physiological Concentrations of the Isoflavonoid Genistein in Androgen-Dependent LNCaP Cells Is Mediated by Estrogen Receptor βEuropean Urology, 2004
- Molecular determinants of resistance to antiandrogen therapyNature Medicine, 2003
- Androgen receptor: A key molecule in the progression of prostate cancer to hormone independenceJournal of Cellular Biochemistry, 2003
- The Role of the Androgen Receptor in Prostate CancerCritical Reviews™ in Eukaryotic Gene Expression, 2002
- Troglitazone Suppresses Cell Growth of Myeloid Leukemia Cell Lines by Induction of p21WAF1/CIP1 Cyclin-Dependent Kinase InhibitorBiochemical and Biophysical Research Communications, 1999
- Androgen receptor gene amplification: A novel molecular mechanism for endocrine therapy resistance in human prostate cancerScandinavian Journal of Clinical and Laboratory Investigation, 1996
- On the Reactivity of the Exocyclic Double Bond in 5-Arylidene-3-aryl-2,4-thiazolidinediones; Their Reaction with Diazoalkanes, p-Thiocresol and PiperidineJournal of the American Chemical Society, 1960