title: Mechanistic studies of the effects of the retinoid N-(4-hydroxyphenyl)retinamide on prostate cancer cell growth and apoptosis.
abstract: 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 microM 4-HPR. Furthermore, increasing the R1881 concentration in the presence of 2.0 microM 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.
authors: Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston 77030-4095, USA.
authors: J C
authors: JC
authors: Shen
authors: T T
authors: TT
authors: Wang
authors: S
authors: S
authors: Chang
authors: S D
authors: SD
authors: Hursting
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle; D004273:DNA, Neoplasm / Q000032:analysis; D004354:Drug Screening Assays, Antitumor; D017313:Fenretinide / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D019254:Genes, bcl-2; D006801:Humans; D008297:Male; D015741:Metribolone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000096:biosynthesis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051028:bcl-2-Associated X Protein
chemical_list: D000728:Androgens; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C494826:BAX protein, human; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051028:bcl-2-Associated X Protein; D017313:Fenretinide; D015741:Metribolone; D017430:Prostate-Specific Antigen