Abstract
Androgen and androgen receptor (AR)-mediated signaling are crucial for the development of prostate cancer. Identification of novel and naturally occurring phytochemicals that target androgen and AR signaling from Oriental medicinal herbs holds exciting promises for the chemoprevention of this disease. In this article, we report the discovery of strong and long-lasting antiandrogen and AR activities of the ethanol extract of a herbal formula (termed KMKKT) containing Korean Angelica gigas Nakai (AGN) root and nine other Oriental herbs in the androgen-dependent LNCaP human prostate cancer cell model. The functional biomarkers evaluated included a suppression of the expression of prostate-specific antigen (PSA) mRNA and protein (IC50, approximately 7 microg/mL, 48-hour exposure) and an inhibition of androgen-induced cell proliferation through G1 arrest and of the ability of androgen to suppress neuroendocrine differentiation at exposure concentrations that did not cause apoptosis. Through activity-guided fractionation, we identified decursin from AGN as a novel antiandrogen and AR compound with an IC50 of approximately 0.4 microg/mL (1.3 micromol/L, 48-hour exposure) for suppressing PSA expression. Decursin also recapitulated the neuroendocrine differentiation induction and G1 arrest actions of the AGN and KMKKT extracts. Mechanistically, decursin in its neat form or as a component of AGN or KMKKT extracts inhibited androgen-stimulated AR translocation to the nucleus and down-regulated AR protein abundance without affecting the AR mRNA level. The novel antiandrogen and AR activities of decursin and decursin-containing herbal extracts have significant implications for the chemoprevention and treatment of prostate cancer and other androgen-dependent diseases.
Highlights
Prostate cancer is second only to lung cancer as the cause of cancer deaths in American men, responsible for an estimated 30,000 deaths per year [1]
The growth suppression effect was accompanied by G1 arrest (Table 1)
Because androgen receptor (AR) function is necessary for prostate-specific antigen (PSA) transcription, we analyzed by immunoblot whether KMKKT decreased AR protein abundance and found that treatment for 24 hours significantly decreased AR protein level (Fig. 1D). These results indicate that the suppressing action of KMKKT on PSA protein level was largely mediated by decreasing PSA mRNA transcript abundance, which was accompanied by decreased AR protein level without changing the level of AR mRNA
Summary
Prostate cancer is second only to lung cancer as the cause of cancer deaths in American men, responsible for an estimated 30,000 deaths per year [1]. Only some taxane drugs have shown limited efficacy for advanced prostate cancer [5]. All of these treatments cause significant side effects. Targeting androgen and AR signaling represents a rational strategy for the chemoprevention of prostate cancer [6, 7]. As a proof of concept, a clinical trial with finasteride (Proscar), which inhibits 5a-reductase II within the prostate gland, had shown a significant reduction of total prostate cancer incidence [8]. Prostate cancer that developed in subjects in the intervention group seemed to be more advanced in tumor stages than those from the placebo group, raising doubt about the overall survival benefit of this singletarget approach. Novel agents that target multiple aspects of androgen and AR signaling will be more desirable
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