Iguchi Kazuhiro, Toyama Tomoaki, Ito Tetsuro, Shakui Toshinobu, Usui Shigeyuki, Oyama Masayoshi, Iinuma Munekazu, Hirano Kazuyuki
Laboratories of Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan.
J Androl. 2012 Nov-Dec;33(6):1208-15. doi: 10.2164/jandrol.112.016782. Epub 2012 Jun 14.
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.
雄激素信号的抑制是前列腺癌治疗的一个靶点。白藜芦醇（3,4',5-三羟基茋）已知可抑制雄激素受体（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，以确定一种有效的抗雄激素化合物。白藜芦醇类似物从植物中分离或由白藜芦醇半合成。使用带有MMTV-荧光素酶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'-甲氧基茋）是AR转录活性最有效的抑制剂。与未修饰的对应物相比，在白藜芦醇及其类似物的C-4'位引入甲氧基增加了它们的抗雄激素活性。相反，对3-和/或5-羟基的修饰降低了抗雄激素活性。在LNCaP细胞中，4'-O-甲基白藜芦醇在抑制与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。
