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: J C Shen, T T Wang, S Chang, S D Hursting
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 24 Issue 3 Pg. 160-8 (Mar 1999) ISSN: 0899-1987 [Print] United States
• PMID: 10204800 (Publication Type: Journal Article)

Chemical References

• Androgens
• Antigens, Neoplasm
• Antineoplastic Agents
• BAX protein, human
• DNA, Neoplasm
• Neoplasm Proteins
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• RNA, Messenger
• RNA, Neoplasm
• bcl-2-Associated X Protein
• Fenretinide
• Metribolone
• Prostate-Specific Antigen

Topics

• Androgens (pharmacology)
• Antigens, Neoplasm (biosynthesis, genetics)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Cycle
• DNA, Neoplasm (analysis)
• Drug Screening Assays, Antitumor
• Fenretinide (pharmacology)
• Gene Expression Regulation (drug effects)
• Genes, bcl-2
• Humans
• Male
• Metribolone (antagonists & inhibitors, pharmacology)
• Neoplasm Proteins (biosynthesis, genetics)
• Neoplasms, Hormone-Dependent (metabolism, pathology)
• Prostate-Specific Antigen (biosynthesis, genetics)
• Prostatic Neoplasms (metabolism, pathology)
• Proto-Oncogene Proteins (biosynthesis, genetics)
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis, genetics)
• RNA, Messenger (biosynthesis)
• RNA, Neoplasm (biosynthesis)
• Tumor Cells, Cultured (drug effects)
• bcl-2-Associated X Protein