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Mechanistic studies of the effects of the retinoid N‐(4‐hydroxyphenyl)retinamide on prostate cancer cell growth and apoptosis

To explore the mechanisms underlying the chemopreventive effects of the synthetic retinoid N‐(4‐hydroxyphenyl)retinamide (4‐HPR) in prostate cancer, we evaluated the anti‐proliferative and apoptosis‐inducing effects of 4‐HPR in the androgen‐sensitive human prostate cancer cell line LNCaP. 4‐HPR decreased the number of viable LNCaP cells (as measured by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay) in a dose‐dependent manner. Although 4‐HPR exerted a modest G1 cell‐cycle block (as determined by flow cytometry), its effect on reduced cell number appeared to result primarily from induction of apoptosis (as measured by an enzyme‐linked immunosorbent assay and flow‐cytometric assays). The mitogenic effects of R1881, a non‐metabolizable androgen that potently induces LNCaP cell proliferation, was completely blocked by greater than 0.5 μM 4‐HPR. Furthermore, increasing the R1881 concentration in the presence of 2.0 μM 4‐HPR increased apoptotic cell death. 4‐HPR decreased prostate‐specific antigen (PSA) protein levels in conditioned medium and decreased PSA mRNA expression. 4‐HPR also decreased the ratio of bcl‐2 to bax mRNA expression in LNCaP cells by approximately 45%, indicating that the apoptotic effects of 4‐HPR may be mediated, at least in part, by alterations in the bcl‐2/bax–regulated apoptotic pathway. N‐acetylcysteine (4 mM) completely blocked the anti‐proliferative and apoptotic‐inducing effects of 4‐HPR, suggesting that an oxidative mechanism may be involved. We concluded that (i) 4‐HPR exerts growth‐suppressive and apoptotic effects on LNCaP cells, (ii) 4‐HPR can interact with androgen to suppress proliferation and induce apoptosis, (iii) the apoptotic effects of 4‐HPR may be mediated in part by the bcl‐2/bax pathway, and (iv) a pro‐oxidant mechanism may contribute to the anti‐proliferative and apoptotic‐inducing effects of 4‐HPR. Mol. Carcinog. 24:160–168, 1999. © 1999 Wiley‐Liss, Inc.