Pharmacological Research, 2013, 79(1):13-20.

Modulators of estrogen receptor inhibit proliferation and migration of prostate cancer cells

Margherita Piccolella, Valeria Crippa, Elio Messi, et al

Sezione di Biomedicina e Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Italy; Neuroscience Program, Wellesley College, Wellesley, MA, USA

In the initial stages, human prostate cancer (PC) is an androgen-sensitive disease, which can be pharmacologically controlled by androgen blockade. This therapy often induces selection of androgen-independent PC cells with increased invasiveness. We recently demonstrated, both in cells and mice, that a testosterone metabolite locally synthetized in prostate, the 5α-androstane-3β, 17β-diol (3β-Adiol), inhibits PC cell proliferation, migration and invasion, acting as an anti-proliferative/anti-metastatic agent. 3β-Adiol is unable to bind androgen receptor (AR), but exerts its protection against PC by specifically interacting with estrogen receptor beta (ERβ). Because of its potential retro-conversion to androgenic steroids, 3β-Adiol cannot be used "in vivo", thus, the aims of this study were to investigate the capability of four ligands of ERβ (raloxifen, tamoxifen, genistein and curcumin) to counteract PC progression by mimicking the 3β-Adiol activity. Our results demonstrated that raloxifen, tamoxifen, genistein and curcumin decreased DU145 and PC3 cell proliferation in a dose-dependent manner; in addition, all four compounds significantly decreased the detachment of cells seeded on laminin or fibronectin. Moreover, raloxifen, tamoxifen, genistein and curcumin-treated DU145 and PC3 cells showed a significant decrease in cell migration. Notably, all these effects were reversed by the anti-estrogen, ICI 182,780, suggesting that their actions are mediated by the estrogenic pathway, via the ERβ, the only isoform present in these PCs. In conclusion, these data demonstrate that by selectively activating the ERβ, raloxifen, tamoxifen, genistein and curcumin inhibit human PC cells proliferation and migration favoring cell adesion. These synthetic and natural modulators of ER action may exert a potent protective activity against the progression of PC even in its androgen-independent status.

英国《药理研究》，2014年1月

雌激素受体的调节剂抑制前列腺癌细胞的增殖和迁移

玛格丽特 皮考蕾拉，瓦莱里娅 克里帕， 埃利奥 梅西，等

意大利米兰大学内分泌学，生物医学和药理学，分子科学学院； 美国韦尔斯利学院神经科学项目

在初始阶段，人体前列腺癌 (PC) 是一种雄激素敏感性疾病，可以被雄激素全阻断剂药物控制。这种疗法通常诱导选定的雄激素非依赖性 PC 细胞的侵袭性增加。我们最近发现，在细胞和小鼠中，在前列腺局部睾丸酮代谢物制备的，5 α-雄甾烷-3β,17 β-二醇，抑制了 PC 细胞增殖、 迁移和侵袭，作为抗-增殖/抗-转移性药剂。3β-Adiol 不能与雄激素受体 (AR)成键，但能通过与雌激素受体 β （ERβ） 相互影响发挥 抗PC的作用。由于其潜在的恢复-转换到雄激素类固醇，3β-Adiol 不能在"体内"使用，因此，本研究的目的是探究ERβ的四个配体（钙稳、 三苯氧胺、 金雀异黄素和姜黄素）如何通过模仿 3β-Adiol 的活性来抵抗 PC 的发展。我们的研究结果表明钙稳、 三苯氧胺、 金雀异黄素和姜黄素降低了 DU145 和 PC3 细胞的增殖以剂量依赖的方式；此外，所有的四种化合物显著降低了细胞接种于层粘连蛋白和纤维粘连蛋白的分离。此外，钙稳，三苯氧胺、 金雀异黄素和姜黄素治疗的 DU145 细胞和 PC3 细胞在细胞迁移时表现出明显降低。值得注意的是，所有这些影响被抗雌激素ICI182,780逆转，这表明它们的活性通过雌激素途径， 由存在于PC细胞中唯一的异构体ERβ 调节。总之，这些数据表明，通过选择性地激活 ERβ，钙稳，三苯氧胺、 金雀异黄素和姜黄素抑制人体 PC 细胞增殖和迁移。这些ER 活性的合成和天然调节剂可能发挥强效的保护活性抑制甚至处于雄激素非依赖性状态的PC的发展。