A novel class of pyranocoumarin anti–androgen receptor signaling compounds

Abstract

Androgen and the androgen receptor (AR) -mediated signaling are crucial for prostate cancer development. Novel agents that can inhibit AR signaling in liganddependent and ligand-independent manners are desirable for the chemoprevention of prostate carcinogenesis and for the treatment of advanced prostate cancer. We have shown recently that the pyranocoumarin compound decursin from the herb Angelica gigas possesses potent anti-AR activities distinct from the anti -androgen bicalutamide. Here, we compared the anti-AR activities and the cell cycle arrest and apoptotic effects of decursin and two natural analogues in the androgen-dependent LNCaP human prostate cancer cell culture model to identify structure-activity relationships and mechanisms. Decursin and its isomer decursinol angelate decreased prostatespecific antigen expression with IC 50 of f1 Mmol/L. Both inhibited the androgen-stimulated AR nuclear translocation and transactivation, decreased AR protein abundance through proteasomal degradation, and induced G 0/1 arrest and morphologic differentiation. They also induced caspase-mediated apoptosis and reactive oxygen species at higher concentrations. Furthermore, they lacked the agonist activity of bicalutamide in the absence of androgen and were more potent than bicalutamide for suppressing androgen-stimulated cell growth. Decursinol, which does not contain a side chain, lacked the reactive oxygen species induction and apoptotic activities and exerted paradoxically an inhibitory and a stimulatory effect on AR signaling and cell growth. In conclusion, decursin and decursinol angelate are members of a novel class of nonsteroidal compounds that exert a long-lasting inhibition of both ligand-dependent and ligand-independent AR signaling. The side chain is critical for sustaining the anti-AR activities and the growth arrest and apoptotic effects. [Mol Cancer Ther 2007;6(3):907 -17]

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.…”

UltrafineAngelica gigasPowder Normalizes Ovarian Hormone Levels and Has Antiosteoporosis Properties in Ovariectomized Rats: Particle Size Effect

“…13 In addition, several studies have addressed the effects of decursin and its derivatives on the prevention and mitigation of chronic health disorders. 14 It is well known that coumarin derivatives have estrogenic activity, since they bind to intracellular receptors for estradiol and progesterone.…”

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

“…6A), is one of the most prevalent compounds in the roots of Korean A. gigas (Yim et al, 2005). It was suggested previously that the side chain of decursin mediates its anticancer activity against hormone-refractory DU145 prostate cancer cells (Yim et al, 2005), and the side chain of decursin was shown to confer anti-AR activity in LNCaP prostate cancer cells (Guo et al, 2007). In this study, decursinol lacked the properties of decursin; it had no effect on Wnt3aCM-induced CRT, the intracellular ␤-catenin level, or the expression of ␤-catenin-dependent genes in HEK293 reporter and PC3 cells.…”

“…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). In the present study, we identified decursin as an inhibitor of the Wnt/␤-catenin pathway using cell-based small-molecule screening.…”