Prostate cancer is the most frequently diagnosed cancer in American men and the second leading cause of male cancer death. Antiandrogens have been used with castration to prevent the progression of prostate cancer. However, cancer relapse often occurs within 2-3 years in patients who received this therapy. This has prompted interest in developing better antiandrogens for prostate cancer treatment. Traditional Chinese Herbal Medicines (TCHM) have been shown to block recurrent prostate cancer growth. In our preliminary study, using a newly-developed androgen receptor (AR) and androgen receptor co-activator (ARA)-mediated transactivation assay, it was found that some extracts from TCHM inhibited AR-induced gene activation, suggesting TCHM is an excellent source to search for new antiandrogen drugs. A cell-based androgen/AR activation assay developed from this study is advantageous in discovering antiandrogens that exert their inhibitory function at different stages of an androgen-induced gene activation. Performing this assay could lead to the discovery of potentially new and different antiandrogen drugs. Conventional antiandrogens only interfere with androgen and AR binding, such as HF (hydroxyflutamide) or casodex (bicalutamide). In this application we propose to develop a high throughput 96-well format AR/ARA transactivation assay using three prostate cancer cell lines: DU145, PC3 and LNCaP. In collaboration with our corporate partner, Plantaceutica Inc. (Chapel Hill, NC), a large number of extracts and compounds from TCHM that are known to possess ingredients with potential antiandrogen and androgenic activities will be screened. Compounds from TCHM extracts with effects to block wild type AR and mutant AR transactivation in all three human prostate cancer cell models will be further tested in a proliferation assay using androgen-sensitive prostate cancer, LNCaP cells to assess their biological efficacy in suppressing prostate cancer cell growth. Compounds discovered by our study with antiandrogenic or androgenic activities will have great potential to be developed into new drugs that will improve the treatment of prostate cancer patients and other androgen related disorders.
Thesaurus Terms: androgen inhibitor, androgen receptor, bioassay, drug screening /evaluation, high throughput technology, hormone regulation /control mechanism, plant extract, technology /technique development, tissue /cell culture folk medicine, receptor expression neoplastic cell
