Exisulind and related compounds inhibit expression and function of the androgen receptor in human prostate cancer cells.

Abstract

In recent studies, we found that sulindac sulfide (SS), exisulind, CP248, and CP461 induce growth inhibition and apoptosis in a series of human prostate cancer cell lines, irrespective of cyclooxygenase expression, p53 mutations, or bcl-2 overexpression. Exisulind also inhibited the growth of the androgen-dependent LNCaP human prostate cancer cell line when grown as a xenograft in nude mice. This study demonstrates that doses of these compounds that induce growth inhibition and apoptosis in LNCaP cells also cause decreased prostate-specific antigen (PSA) secretion and decreased cellular levels of PSA. These effects appear to be a result, at least in part, of inhibition of the androgen receptor (AR) signaling pathway because the treated cells also display decreases in the level of the AR protein and mRNA and inhibition of transcription of an AR promoter luciferase reporter in transient transfection assays. SS and exisulind were more effective in inhibiting the expression of PSA and the AR than CP248 or CP461, apparently because of differential effects of these compounds on specific transcription factors. These findings suggest that the growth inhibition by these compounds in human prostate cancer cells may be mediated, in part, by inhibition of AR signaling. Thus, these compounds may provide a novel approach to the prevention and treatment of human prostate cancer.

• Authors: Jin T E Lim, Gary A Piazza, Rifat Pamukcu, W Joseph Thompson, I Bernard Weinstein
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 9 Issue 13 Pg. 4972-82 (Oct 15 2003) ISSN: 1078-0432 [Print] United States
• PMID: 14581372 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (5-fluoro-2-methyl-1-(4-pyridyl)methylene-3-(N-benzyl)-indene)-acetamide hydrochloride
• Antineoplastic Agents
• HSP70 Heat-Shock Proteins
• Phosphodiesterase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• RNA, Messenger
• Receptors, Androgen
• Tumor Suppressor Protein p53
• Sulindac
• Luciferases
• Prostate-Specific Antigen
• sulindac sulfone

Topics

• Antineoplastic Agents (pharmacology)
• Blotting, Northern
• Cell Line, Tumor
• Down-Regulation
• Genes, Reporter
• HSP70 Heat-Shock Proteins (metabolism)
• Humans
• Immunoblotting
• Luciferases (metabolism)
• Male
• Mutation
• Neoplasm Transplantation
• Phosphodiesterase Inhibitors (pharmacology)
• Plasmids (metabolism)
• Promoter Regions, Genetic
• Prostate-Specific Antigen (metabolism)
• Prostatic Neoplasms (metabolism)
• Protein Binding
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• RNA, Messenger (metabolism)
• Receptors, Androgen (biosynthesis)
• Signal Transduction
• Sulindac (analogs & derivatives, pharmacology)
• Time Factors
• Transcription, Genetic
• Transfection
• Tumor Suppressor Protein p53 (genetics)
• Up-Regulation