N-(4-HYDROXYPHENYL) RETINAMIDE INDUCES CELL-CYCLE SPECIFIC GROWTH-INHIBITION IN PC3 CELLS

The synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) has been demonstrated to inhibit the development of primary and metastatic neoplasms in several animal models. In order to investigate the effect of 4-HPR on human prostate adenocarcinoma, we designed a series of in vitro experiments with the PC3 cell line to evaluate effects on proliferation, cell cycle kinetics, and c-myc mRNA expression. 4-HPR demonstrated cytoxicity only at the supraphysiologic concentration of 10.0 mu M. However, asynchronously growing cells exposed to 1 mu M 4-HPR demonstrated a 51% reduction in proliferation rate, associated with an accumulation of cells in the G0/G1 phase of the cell cycle. PC3 cells synchronized with serum deprivation or aphidicoline exhibited significant decreases in DNA synthesis when treated with 1 mu M 4-HPR. Additionally, these cells were found to accumulate in G0/G1 and S phase. Northern blots indicated a significant decrease in c-myc mRNA expression in asynchronously growing cells with continuous administration of 1 mu M 4-HPR for 6 days. These data suggest that 4-HPR can inhibit growth of PC3 cells as a consequence of a block in cell cycle transition from G1 to S phase at a concentration of 1 mu M, and that this inhibition is associated with a suppression of c-myc gene expression. (C) 1994 Wiley-Liss, Inc.