Antagonists of retinoic acid receptors (RARs) are potent growth inhibitors of prostate carcinoma cells

Novel synthetic antagonists of retinoic acid receptors (RARs) have been developed. To avoid interference by serum retinoids when testing these compounds, we established serum-free grown sub-lines (>3 years) of the prostate carcinoma lines LNCaP, PC3 and DU145. A high affinity pan-RAR antagonist (AGN194310, K-d for binding to RARs = 2-5 nM) inhibited colony formation (by 50%) by all three lines at 16-34 nM, and led to a transient accumulation of flask-cultured cells in G1 followed by apoptosis. AGN194310 is 12-22 fold more potent than all-trans retinoic acid (ATRA) against cell lines and also more potent in inhibiting the growth of primary prostate carcinoma cells. PC3 and DU145 cells do not express RAR beta, and an antagonist with predominant activity at RAR beta and RAR gamma (AGN194431) inhibited colony formation at concentrations (similar to 100 nM) commensurate with a K-d value of 70 nM at RAR gamma. An RAR alpha antagonist (AGN194301) was less potent (IC50 similar to 200 nM), but was more active than specific agonists of RAR alpha and of beta gamma. A component(s) of serum and of LNCaP-conditioned medium diminishes the activity of antagonists: this factor is not the most likely candidates IGF-1 and EGF. In vitro studies of RAR antagonists together with data from RAR-null mice lead to the hypothesis that RAR gamma -regulated gene transcription is necessary for the survival and maintenance of prostate epithelium. The increased potencies of RAR antagonists, as compared with agonists, suggest that antagonists may be useful in the treatment of prostate carcinoma. (C) 2001 Cancer Research Campaign.