MELANOMA CELL-GROWTH INHIBITION AND MELANOCORTIN RECEPTOR DOWN-REGULATION INDUCED BY SELECTIVE AND NONSELECTIVE RETINOIDS

The purpose of this study was to investigate the effects of retinoid a nalogues with different retinoid receptor specifity on the growth of h uman D10 and Cloudman S91 mouse melanoma cells. We compared the growth inhibitory effects with the ability of retinoids to downregulate cell surface expression of the melanocortin receptor (MC1-R). Retinoic aci d receptor (RAR)-gamma-selective retinoids exerted the most prominent growth effects, with up to 68% and 69% inhibition in D10 and S91 cells , respectively. A retinoid X receptor (RXR)-selective compound inhibit ed cell growth by only 14% and 23% in D10 and S91 cells, respectively. Growth inhibition by RAR alpha- and RAR beta-selective compounds was below 10% in both cells. In D10 cells, MC1-R downregulation was also i nduced most effectively by an RAR gamma-selective retinoid (84% relati ve to controls). RAR alpha-, RAR beta- and RXR-selective agonists indu ced only 16-24% MC1-R downregulation in these cells. The pattern for M C1-R downregulation was completely different in S91 cells. The RXR-sel ective compound was the most active (85%), followed by the RAR alpha-s elective agonist (58%), the RAR gamma-selective compound (47%), and fi nally by the RAR beta-selective agonist (29%). We conclude that RAR ga mma-selective retinoids may have potential as therapeutic agents in me lanoma. Different selectivity profiles for growth inhibition and MC1-R downregulation in S91 cells suggest that these two retinoid effects a re not directly dependent on each other. (C) 1998 Lippincott-Raven Pub lishers.