Induction of apoptosis by N-(4-hydroxyphenyl)retinamide and its association with reactive oxygen species, nuclear retinoic acid receptors, and apoptosis-related genes in human prostate carcinoma cells

The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) has been shown to induce apoptosis in various malignant cells including human prostate car cinoma cells (HPC), We examined several possible mechanisms by which I HPR could induce apoptosis in HPC cells. 4HPR exhibited concentration- and time -dependent decrease in cell number both in androgen-dependent (LNCaP) and - independent (DU145 and PC-3) cells. The 4HPR concentrations causing 50% dec rease in cell number in LNCaP, DU145, and PC-3 cultures were 0.9 +/- 0.16, 4.4 +/- 0.45, and 3.0 +/0 1.0 mu M, respectively, indicating that LNCaP cel ls were more sensitive to 4HPR than the other cells. 4HPR-induced apoptosis in all three cell lines was evidenced by increased enzymatic labeling of D NA breaks and formation of a DNA ladder. 4HPR increased the level of reacti ve oxygen species, especially in LNCaP cells. 4HPR-induced apoptosis could be suppressed in LNCaP cells by antioxidant and in DU145 cells by a nuclear retinoic acid receptor-specific antagonist, suggesting the involvement of reactive oxygen species or retinoic acid receptors in mediating apoptosis i nduced by 4HPR in the different HPC cells, Furthermore, 4HPR modulated the expression levels of some apoptosis-related gene (p21, c-myc, and c-jun), w hich may also contribute to the induction of apoptosis by 4HPR in HPC cells .