IN-VITRO ANTI-INVASIVE EFFECTS OF N-(4-HYDROXYPHENYL)-RETINAMIDE ON HUMAN PROSTATIC ADENOCARCINOMA

Components of malignant invasion, namely cellular adhesion, motility, and proteolytic capability provide potential sites of pharmacological intervention for malignancy. In this study, a series of experiments we re performed to examine the effects of N-(4-hydroxyphenyl) retinamide (4-HPR, Fenretinide) on cellular adhesion, motility and proteolytic ac tivity of established prostate cancer cell lines, TSU-PR 1 and PC-3. R adio-adhesion study showed that the treatment of TSU-PR 1 and PC-3 cel ls with 10(-6)M of 4-HPR resulted in a 32% and 37% reduction (p < 0.05 ), respectively in the cellular adhesion to the matrigel extract Radio migration assay also demonstrated that 4-HPR concentration of 10(-6)M reduced the cellular motility by 29% in TSU-PR1 and 28% in PC-3 cells (p < 0.05). Spectrolyse PL indirect chromogenic assay revealed an incr ease in total activatable uPA activity (TSU-PR 1: 25%, PC-3: 32%, P < 0.05), while Spectrolyse UK direct assay demonstrated a mild, but a st atistically significant reduction (PC-3: 5%, TSU-PRI:9% P < 0.05) in a ctive uPA activity. Northern analysis and ELISA assays showed that 4-H PR at 10(-6)M enhances the expression of type I plasminogen activator inhibitor (PAI-I). Type IV collagenase western blot analysis and densi tometry did not demonstrate suppr ession of the enzyme secretion, but in fact suggested increased translation of the enzyme when treated wit h 10(-6)M concentration of fenretinide. The results of this study demo nstrate that 4-HPR inhibits in vitro cellular adhesion and motility of human prostate adenocarcinoma cell lines, TSU-PR1 and PC-3. Additiona lly, uPA and PAI-1 assay results suggest that 4-HPR may impair active uPA's proteolytic activity while upregulating the expression of total activatable uPA and PAI-1. The results of this study therefore support 4-HPR's role as a potential anti-invasive agent.