Antiandrogenic Activity of Resveratrol Analogs in Prostate Cancer LNCaP Cells
Antiandrogenic Activity of Resveratrol Analogs in Prostate Cancer LNCaP Cells
复制标题
DOI：
10.2164/jandrol.112.016782
复制
发表时间：
2012-11-01
影响因子：
--
通讯作者：
Hirano, Kazuyuki
中科院分区：
文献类型：
--
作者：
Iguchi, Kazuhiro;Toyama, Tomoaki;Hirano, Kazuyuki
雄激素信号传导的抑制是治疗前列腺癌的治疗靶点。已知白藜芦醇（3，4 '，5-三羟基芪）抑制雄激素受体（AR）的功能。在本研究中，我们研究了白藜芦醇类似物的抗雄激素活性，以确定一个有效的抗雄激素化合物。白藜芦醇类似物是从植物中分离的或从白藜芦醇中半合成的。使用MMTV-luc报告质粒的荧光素酶测定法在前列腺癌LNCaP细胞中测量AR转录活性。在所测试的白藜芦醇类似物中，4 '-O-甲基白藜芦醇（3，5-二羟基-4'-甲氧基芪）是AR转录活性的最有效抑制剂。在白藜芦醇及其类似物的C-4'端引入甲氧基后，其抗雄激素活性较未修饰的白藜芦醇及其类似物有所增强。相反，3-和/或5-羟基的修饰降低了抗雄激素活性。4 '-O-甲基白藜芦醇在抑制LNCaP细胞中与AR信号相关的Akt磷酸化方面比白藜芦醇更有效。白藜芦醇中的羟基通过调节AR转录活性在其抗雄激素作用中起关键作用。
The suppression of androgen signaling is a therapeutic target for the treatment of prostate cancer. Resveratrol (3,4',5-trihydroxystilbene) is known to inhibit the function of the androgen receptor (AR). In the present study, we investigated the antiandrogenic activities of resveratrol analogs in order to identify a potent antiandrogen compound. Resveratrol analogs were isolated from plants or were semisynthesized from resveratrol. AR transcriptional activity was measured in prostate cancer LNCaP cells using a luciferase assay with the MMTV-luc reporter plasmid. Among the resveratrol analogs tested, 4'-O-methylresveratrol (3,5-dihydroxy-4'-methoxystilbene) was the most effective inhibitor of AR transcriptional activity. Introduction of a methoxy group to the C-4' of resveratrol and its analogs increased their antiandrogenic activity compared with the unmodified counterparts. Conversely, modification of the 3- and/or 5-hydroxyl groups reduced the antiandrogenic activity. 4'-O-methylresveratrol was more effective than resveratrol in inhibiting Akt phosphorylation, which is related to AR signaling, in LNCaP cells. The hydroxyl groups in resveratrol play a key role in their antiandrogenic effect by modulating AR transcriptional activity.