Potent Antiandrogen and Androgen Receptor Activities of anAngelica gigas–Containing Herbal Formulation: Identification of Decursin as a Novel and Active Compound with Implications for Prevention and Treatment of Prostate Cancer

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 (IC 50 , f7 Mg/mL, 48-hour exposure) and an inhibition of androgen-induced cell proliferation through G 1 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 IC 50 of f0.4 Mg/mL (1.3 Mmol/L, 48-hour exposure) for suppressing PSA expression. Decursin also recapitulated the neuroendocrine differentiation induction and G 1 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. (Cancer Res 2006; 66(1): 453-63)

Herbal Extract ofWedelia chinensisAttenuates Androgen Receptor Activity and Orthotopic Growth of Prostate Cancer in Nude Mice

“…For various reasons, the most important of which may be public acceptance, natural products are preferred over synthetic agents for this role. In recent years, much progress has been made in identification of novel prostate cancer chemopreventive and chemotherapeutic agents from natural products (8,9,(26)(27)(28)(29)(30)(31)(32)(33)(34). It should be noted that luteolin and apigenin, two major active compounds of W. chinensis, have been independently reported as having potential for prostate cancer treatment through different mechanisms.…”

Anti-Inflammatory Effects of an Ethanol Extract of Angelica gigas in a Carrageenan-Air Pouch Inflammation Model

“…Recently, several coumarin derivatives, including decursins, decursinol, decursinol angelate, nodakenin, nodakenetin, and umbelliferone, were isolated from Angelica gigas [7,19,24]. Additional pharmacological effects of these derivatives include anti-tumor activities [2,17,22], antiplatelet aggregation [25], Helicobacter pylori-suppression [3], neuroprotection [20], and memory enhancement [21,43].…”

Decursin Suppresses Human Androgen-Independent PC3 Prostate Cancer Cell Proliferation by Promoting the Degradation of β-Catenin

“…Recently, it was shown that decursin inhibits growth and promotes cell death in both androgen-dependent and -independent prostate cancer cells (Yim et al, 2005). Jiang et al (2006) suggested that decursin inhibits the proliferation of androgen-dependent LNCaP cells reporter cells were incubated with indicated concentrations of decursinol in the presence of Wnt3a CM. After 15 h, luciferase activity was determined.…”

“…Decursin has a cytotoxic effect on leukemia cells through a mechanism involving protein kinase C and reactive oxygen species, and it has antitumor activity in mice inoculated with sarcoma cells (Lee et al, 2003b;Kim et al, 2005). It has been reported that decursin suppresses growth and promotes apoptosis in human prostate carcinoma cells (Yim et al, 2005;Jiang et al, 2006). Moreover, the (CH 3 ) 2 -CϭCH-COO-side chain of decursin, which is replaced with an OH group in decursinol, seems to be necessary for its anticancer activity (Yim et al, 2005;Guo et al, 2007).…”

“…Because decursin was identified recently as a chemopreventive agent against prostate carcinoma cells (Yim et al, 2005;Jiang et al, 2006), we tested whether decursin also suppresses the Wnt/␤-catenin pathway in prostate cancer cells, which frequently show abnormally high levels of intracellular ␤-catenin (Barker and Clevers, 2000). Androgen-independent PC3 prostate cancer cells were transiently transfected with TOPFlash followed by incubation with increasing amounts of decursin.…”