A synthetic decursin analog with increased in vivo stability suppresses androgen receptor signaling in vitro and in vivo.
A synthetic decursin analog with increased in vivo stability suppresses androgen receptor signaling in vitro and in vivo.
复制标题
体内稳定性增强的合成 decursin 类似物可抑制体外和体内雄激素受体信号传导。
DOI：
10.1007/s10637-011-9738-x
复制
发表时间：
2012
影响因子：
3.4
通讯作者：
Jiang,Cheng
中科院分区：
文献类型：
--
作者：
Zhang,Yong;Shaik,AhmadAli;Xing,Chengguo;Chai,Yubo;Li,Li;Zhang,Jinhui;Zhang,Wei;Kim,Sung-Hoon;Lü,Junxuan;Jiang,Cheng
Targeting androgen receptor (AR) signaling with agents distinct from current antagonist drugs remains a rational approach to the prevention and treatment of prostate cancer (PCa). Our previous studies have shown that decursin and isomer decursinol angelate (DA), isolated from the Korean medicinal herbAngelica gigasNakai, interrupt AR signaling and possess anti-PCa activitiesin vitro.In the LNCaP PCa cell model, these pyranoccoumarin compounds exhibit properties distinct from currently used antagonists (e.g., Casodex). However, both are rapidly de-esterified to decursinol, a partial AR agonist.We report here that a synthetic decursin analog, decursinol phenylthiocarbamate (DPTC), has greaterin vivostability than the parent compounds. DPTC-decursinol conversion was undetectable in mice. Furthermore, in LNCaP cells, DPTC decreased prostate specific antigen (PSA) expression, down-regulated AR abundance and mRNA and inhibited AR nuclear translocation. The effect of DPTC on AR and PSA mRNA and protein abundance was also observed in VCaP cells expressing wild type AR. DPTC inhibited growth of both PCa cell lines through G1cell cycle arrest and apoptosis, as did decursin and DA. Furthermore, i.p. administration of DPTC for 3 weeks suppressed the expression of AR target genes probasin and Nkx3.1 in mouse prostate glands. Overall, our data suggest that DPTC represents a prototype lead compound for development ofin vivostable and active novel decursin analogs for the prevention or therapy of PCa.
