De Santi Mauro, Carloni Elisa, Galluzzi Luca, Diotallevi Aurora, Lucarini Simone, Magnani Mauro, Brandi Giorgio
Department of Biomolecular Sciences, University of Urbino Carlo Bo, Via Saffi, 2, 61029 Urbino, Italy.
Anticancer Agents Med Chem. 2015;15(7):896-904. doi: 10.2174/1871520615666150121123053.
Natural products such as aromatase inhibitors have been the object of growing attention in recent years because of their potential to inhibit aromatase with fewer side effects and the possible translation of their current use as chemotherapeutic agents to future clinical applications in breast cancer chemoprevention. We have previously investigated CTet, a novel anticancer agent obtained from the broccoli-derived compound indole-3- carbinol (I3C), that shows great anticancer potential in both in vitro and in vivo studies. Here we evaluated the potential of CTet as a chemopreventive agent in aromatase expressing MCF-7/AROM-1 breast cancer cells. The testosterone (TE) aromatization in estradiol (E2) was indirectly evaluated in terms of inhibition of TE-induced cell proliferation, ERα phosphorylation/activation and Bcl-2 and IGF-1R ERE-regulated protein accumulation. Our results showed that CTet inhibited TE-driven ERα phosphorylation of both cytosolic and nuclear ERα pools, suggesting an inhibitory effect of TE aromatization in E2. CTet did not inhibit E2-driven nuclear ERα phosphorylation, but partially inhibited E2-driven cytosolic ERα phosphorylation. Moreover, CTet inhibited Bcl-2 and IGF-1R accumulation induced by TE but not that which was induced by E2. A cell-free enzymatic assay showed that CTet did not inhibit aromatase activity directly; however, since CTet treatment induced endoplasmic reticulum stress, the TE aromatization could be affected because the aromatase enzyme is located within the endoplasmic reticulum. Finally, CTet and letrozole synergistically inhibited TE-induced cell proliferation. These results showed the potential of the I3C derivative CTet as a chemopreventive agent that interferes with aromatase activity.
近年来，诸如芳香化酶抑制剂之类的天然产物因其具有抑制芳香化酶的潜力、副作用较少，以及有可能将其目前作为化疗药物的用途转化为未来在乳腺癌化学预防中的临床应用，而受到越来越多的关注。我们之前研究了CTet，一种从西兰花衍生化合物吲哚 - 3 - 甲醇（I3C）中获得的新型抗癌剂，它在体外和体内研究中均显示出巨大的抗癌潜力。在此，我们评估了CTet作为一种化学预防剂在表达芳香化酶的MCF - 7/AROM - 1乳腺癌细胞中的潜力。通过抑制睾酮（TE）诱导的细胞增殖、雌激素受体α（ERα）磷酸化/激活以及Bcl - 2和胰岛素样生长因子 - 1受体（IGF - 1R）雌激素反应元件（ERE）调控的蛋白积累，间接评估了睾酮（TE）向雌二醇（E2）的芳香化作用。我们的结果表明，CTet抑制了TE驱动的胞质和核ERα池的ERα磷酸化，提示TE向E2的芳香化作用受到抑制。CTet不抑制E2驱动的核ERα磷酸化，但部分抑制E2驱动的胞质ERα磷酸化。此外，CTet抑制TE诱导的Bcl - 2和IGF - 1R积累，但不抑制E2诱导的积累。无细胞酶活性测定表明，CTet不直接抑制芳香化酶活性；然而，由于CTet处理诱导了内质网应激，TE的芳香化作用可能会受到影响，因为芳香化酶位于内质网内。最后，CTet和来曲唑协同抑制TE诱导的细胞增殖。这些结果表明I3C衍生物CTet作为一种干扰芳香化酶活性的化学预防剂具有潜力。
