Dihydrotestosterone (DHT) is the most active androgen in the prostate, thus its inhibition is of critical interest in the treatment of prostate cancer. Dutasteride is a novel dual inhibitor of the steroid 5 alpha-reductase (5a-R) enzyme, which catalyzes the conversion of testosterone (T) to the more potent DHT in prostate tissue. In contrast to previously studied inhibitors of 5a-R such as finesteride, dutasteride effectively inhibits both 5a-R isoenzymes in the prostate (5a-R1 and 5a-R2). Dutasteride has been approved for clinical use in treatment of men with benign prostate hyperplasia (BPH) and this year the REDUCE (Reduction by Dutasteride of prostate Cancer Events) clinical trials will begin testing the use of dutasteride for chemoprevention of PCa. Mechanistic data are critically important in the early phases of identifying promising chemopreventive agents and in vitro assays are the first step in this process. Mechanistic data is also useful in developing animal efficacy models and in interpreting in vitro results in these models. Currently, there is no published data on dutasteride’s mechanism of action in prostate cancer cells. To address this, we have assessed dutasteride’s effects in vitro on the growth and proliferation of the androgen responsive LNCaP prostate cancer cell line. Additionally, microarray chip analysis was then performed to identify genes and pathways affected by treatment with dutasteride and expression levels of candidate genes such as CASP7, NKX3.1, PLA2G2A, CDK8, and MDK were confirmed using real time PCR. Many of the genes identified as being regulated by this drug are genes involved in metabolic, cell-cycle, and apoptotic pathways, in addition to the expected genes involved in the androgen signaling pathway. Understanding how dutasteride affects prostate cancer cells at the molecular level will lead to better therapeutic use of this drug in the chemoprevention or possibly treatment of prostate cancer.
[Proc Amer Assoc Cancer Res, Volume 45, 2004]