High Content Screening Using New U2OS Reporter Cell Models Identifies Harmol Hydrochloride as a Selective and Competitive Antagonist of the Androgen Receptor.

摘要: Prostate cancer is the most commonly diagnosed malignancy in men. Its growth mainly relies on activity of androgen receptor (AR), justifying use deprivation therapy as a gold standard treatment for metastatic disease. Inhibition axis using second generation antagonists has improved patients' survival, but systematically confronted to resistance mechanisms, leading median survival that does not exceed 5 years. Counteracting this been object large number investigations, with particular emphasis towards identification new AR inhibitors, whether they antagonize by competitive or non-competitive binding. To end, many high content screens have performed, identify non-steroidal antagonists, variety approaches, reported somewhat controversial results, depending approach and cell model was used screening. In our study, we U2OS osteosarcoma cells stably transfected ARv7 luciferase reporter previously validated screen Prestwick Phytochemical library. The results identified ellipticine, harmol, harmine hydrochloride confirmed hits. Surprisingly, could demonstrate harmol hydrochloride, inhibitor weak signaling, actually antagonist AR, which inhibits VCaP prostate line, at concentrations it did affect negative DU145 PC3 cells. Interestingly, also report first time selective alter other nuclear receptors, such glucocorticoid (GR), progesterone (PR), mineralocorticoid (MR). Additionally, that, conversely enzalutamide, show any agonistic pregnane X (PXR), master regulator drug metabolism. Together, shed light importance cellular context screening antagonists. They further indicate some potential hits were may overlooked.