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 neo plasms in several animal models. In order to investigate the effect of 4-HPR on human prostate adenocarcinoma, we designed a series of in vi tro experiments with the PC3 cell line to evaluate effects on prolifer ation, cell cycle kinetics, and c-myc mRNA expression. 4-HPR demonstra ted cytoxicity only at the supraphysiologic concentration of 10.0 mu M . However, asynchronously growing cells exposed to 1 mu M 4-HPR demons trated a 51% reduction in proliferation rate, associated with an accum ulation of cells in the G0/G1 phase of the cell cycle. PC3 cells synch ronized with serum deprivation or aphidicoline exhibited significant d ecreases 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 asy nchronously growing cells with continuous administration of 1 mu M 4-H PR 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 ass ociated with a suppression of c-myc gene expression. (C) 1994 Wiley-Li ss, Inc.