Wu Wei, Tang Su-Ni, Zhang Yong, Puppala Manohar, Cooper Timothy K, Xing Chengguo, Jiang Cheng, Lü Junxuan
* Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
‡ Department of Biomedical Sciences, Texas Tech University Health Sciences Center, School of Pharmacy, Amarillo, Texas 79106, USA.
Am J Chin Med. 2017;45(8):1773-1792. doi: 10.1142/S0192415X17500963. Epub 2017 Nov 9.
We have previously shown that the ethanol extract of dried Angelica gigas Nakai (AGN) root exerts anticancer activity against androgen receptor (AR)-negative human DU145 and PC-3 prostate cancer xenografts and primary carcinogenesis in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The major pyranocoumarin isomers decursin (D) and decursinol angelate (DA), when provided at equi-molar intake to that provided by AGN extract, accounted for the inhibitory efficacy against precancerous epithelial lesions in TRAMP mice. Since we and others have shown in rodents and humans that D and DA rapidly and extensively convert to decursinol, here we tested whether decursinol might be an in vivo active compound for suppressing xenograft growth of human prostate cancer cells expressing AR. In SCID-NSG mice carrying subcutaneously inoculated human LNCaP/AR-Luc cells overexpressing the wild type AR, we compared the efficacy of 4.5[Formula: see text]mg decursinol per mouse with equi-molar dose of 6[Formula: see text]mg D/DA per mouse. The result showed that decursinol decreased xenograft tumor growth by 75% and the lung metastasis, whereas D/DA exerted a much less effect. Measurement of plasma decursinol concentration, at 3[Formula: see text]h after the last dose of respective dosing regimen, showed higher circulating level in the decursinol-treated NSG mice than in the D/DA-treated mice. In a subsequent single-dose pharmacokinetic experiment, decursinol dosing led to 3.7-fold area under curve (AUC) of plasma decursinol over that achieved by equi-molar D/DA dosing. PK advantage notwithstanding, decursinol represents an active compound to exert in vivo prostate cancer growth and metastasis inhibitory activity in the preclinical model.
我们之前已经表明，干燥的当归（AGN）根乙醇提取物对雄激素受体（AR）阴性的人DU145和PC-3前列腺癌异种移植瘤以及小鼠前列腺转基因腺癌（TRAMP）模型中的原发性致癌作用具有抗癌活性。主要的吡喃香豆素异构体蛇床子素（D）和当归酰蛇床子素（DA），当以与AGN提取物提供的等摩尔摄入量给药时，对TRAMP小鼠的癌前上皮病变具有抑制作用。由于我们和其他人已经在啮齿动物和人类中表明，D和DA会迅速且广泛地转化为蛇床子醇，因此我们在此测试蛇床子醇是否可能是一种在体内抑制表达AR的人前列腺癌细胞异种移植生长的活性化合物。在皮下接种了过表达野生型AR的人LNCaP/AR-Luc细胞的SCID-NSG小鼠中，我们比较了每只小鼠4.5[公式：见原文]mg蛇床子醇与每只小鼠等摩尔剂量6[公式：见原文]mg D/DA的疗效。结果表明，蛇床子醇使异种移植瘤生长减少了75%，并减少了肺转移，而D/DA的作用则小得多。在各自给药方案的最后一剂后3[公式：见原文]小时测量血浆蛇床子醇浓度，结果显示，接受蛇床子醇治疗的NSG小鼠的循环水平高于接受D/DA治疗的小鼠。在随后的单剂量药代动力学实验中，蛇床子醇给药导致血浆蛇床子醇的曲线下面积（AUC）是等摩尔D/DA给药所达到的AUC的3.7倍。尽管有药代动力学优势，但蛇床子醇是一种在临床前模型中发挥体内前列腺癌生长和转移抑制活性的活性化合物。
