Ashok B T, Chen Y, Liu X, Bradlow H L, Mittelman A, Tiwari R K
Department of Microbiology, Immunology, and Medicine, New York Medical College, Valhalla, NY 10595, USA.
Nutr Cancer. 2001;41(1-2):180-7. doi: 10.1080/01635581.2001.9680630.
The use of naturally occurring phytoantiestrogens for prevention and therapy of breast cancer is an alternative to synthetic antiestrogens. We have been examining the mechanism of action of the antiestrogen indole-3-carbinol (I3C), a constituent of compounds present in cruciferous vegetables. I3C abrogates the cell-proliferative effect of 17 beta-estradiol (E2), as observed in several different estradiol-responsive breast cancer cell lines and isolated cell clones. Modulation of E2 activity by I3C, in part, was by the induction of the 2-hydroxylation pathway, one of the two competing hydroxylation pathways of estrone conversion that resulted in the formation of metabolites with antiestrogenic properties. I3C-mediated induction of the 2-hydroxylation pathway correlated with a selective induction of cytochrome P-450 1A1 by I3C in E2-responsive human breast cancer cells. Induction of neither the 2-hydroxylation pathway nor cytochrome P-450 1A1 was observed in estrogen-nonresponsive human breast cancer cells. This selective effect warranted a further search for biochemical targets of I3C related to E2 function. To this end, we observed that E2-mediated phosphorylation of the estrogen receptor is inhibited by I3C. Our results are consistent with the hypothesis that I3C exerts its antiestrogenic effect by intervention in the E2-estrogen receptor signal transduction pathways and by alterations in E2 metabolism that resulted in the formation of metabolites with antiestrogenic activity.
使用天然存在的植物抗雌激素来预防和治疗乳腺癌是合成抗雌激素的一种替代方法。我们一直在研究抗雌激素吲哚 - 3 - 甲醇（I3C）的作用机制，I3C是十字花科蔬菜中所含化合物的一种成分。在几种不同的雌激素反应性乳腺癌细胞系和分离的细胞克隆中观察到，I3C消除了17β - 雌二醇（E2）的细胞增殖作用。I3C对E2活性的调节部分是通过诱导2 - 羟化途径实现的，这是雌酮转化的两种相互竞争的羟化途径之一，该途径导致形成具有抗雌激素特性的代谢产物。I3C介导的2 - 羟化途径的诱导与I3C在E2反应性人乳腺癌细胞中对细胞色素P - 450 1A1的选择性诱导相关。在雌激素无反应性人乳腺癌细胞中未观察到2 - 羟化途径或细胞色素P - 450 1A1的诱导。这种选择性效应促使我们进一步寻找与E2功能相关的I3C的生化靶点。为此，我们观察到I3C抑制了E2介导的雌激素受体磷酸化。我们的结果与以下假设一致，即I3C通过干预E2 - 雌激素受体信号转导途径以及改变E2代谢来发挥其抗雌激素作用，而E2代谢改变导致形成具有抗雌激素活性的代谢产物。
