Selective Androgen Receptor Down-Regulators (SARDs): A New Prostate Cancer Therapy
Abstract
The androgen receptor (AR) plays a key role in the development and progression of prostate cancer Targeting the AR for down-regulation would be a useful strategy for treating prostate cancer, especially hormone-refractory or androgen independent prostate cancer (AIPC). In the present study we showed that the antiestrogen Fulvestrant (ICI 182,780, ICI) effectively suppressed AR expression in several human prostate cancer cells including androgen-independent cells In LNCaP cells, ICI (10 microM) treatment decreased AR mRNA expression by 43% after 24 hours and AR protein expression by approximately 50% after 48 hours We further examined the mechanism of AR down-regulation by ICI in LNCaP cells ICI did not bind to the T877A mutant AR present in the LNCaP cells nor did it promote proteasomal degradation of the AR ICI did not affect AR mRNA or protein half-life However, ICI decreased the activity of an AR promoter-luciferase reporter plasmid transfected into LNCaP cells, suggesting a direct repression of AR gene transcription. As a result of AR down-regulation by ICI, androgen induction of PSA mRNA and protein expression were substantially attenuated. Importantly, LNCaP cell proliferation was significantly inhibited by ICI treatment Following 6 days of ICI treatment a 70% growth inhibition was seen in androgen stimulated LNCaP cells. These data demonstrate that the antiestrogen ICI is a potent AR down-regulator that causes significant inhibition of prostate cancer cell growth. Our study suggests that AR down-regulation by ICI would be an effective strategy for the treatment of all prostate cancer, especially AR-dependent Al PC
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2007
- Accession Number
- ADA475249
Entities
People
- Rumi S. Bhattacharyya
Organizations
- Stanford University