Anti-cancer drugs, 2011, 22(3):253-61.

Additive effects of trastuzumab and genistein on human breast cancer cells

Claus Lattrich, et al

Department of Obstetrics and Gynecology, University Medical Center Regensburg, Regensburg, Germany.

Soy isoflavone genistein, a tyrosine kinase inhibitor and agonist of estrogen receptor-β (ERβ), is known to have antitumoral properties. Given that ERβ often is coexpressed with HER2 in breast cancer, both functions of genistein might be able to enhance the antitumoral action of trastuzumab. In this in-vitro study, we tested whether combined treatment with genistein and trastuzumab exerts additive effects on breast cancer cells. HER2-overexpressing breast cancer cell lines were treated with genistein alone and in combination with trastuzumab. The effects of this treatment on proliferation and gene expression were analyzed. Treatment with high-dose genistein (10 μmol/l) significantly increased the growth-inhibitory effect of trastuzumab on HER2-overexpressing, ERα/β-positive BT-474 breast cancer cells. Combinatory treatment using lower doses of trastuzumab exerted similar effects as a single treatment with standard doses of this drug. In contrast, this effect was absent in ERα-negative SK-BR-3 cells. Similar results were obtained after cotreatment with the ERβ agonist, 2,3-bis(4-hydroxyphenyl)propionitrile. The growth-inhibitory effect of both drugs was accompanied by an increased expression of the putative tumor suppressor ERβ variant, cx, and their combination further elevated mRNA levels of this receptor. In conclusion, genistein significantly enhanced the antitumoral effect of trastuzumab on BT-474 breast cancer cells in vitro. The relevance of these data particularly for women with HER2-overexpressing and ERα/β-positive breast cancer has to be verified in animal or clinical studies.

英国《抗癌药物》，2011年3月

曲妥珠单抗和金雀异黄素对人体乳腺癌细胞的加强性影响

克劳斯 拉瑞慈等

德国雷根斯堡大学医学中心产科学和妇科学院

大豆异黄酮金雀异黄素，一种 酪氨酸激酶抑制剂和雌激素受体-β （ERβ）的激动剂，众所周知具有抗癌特性。鉴于，ERβ 经常与 HER2 在乳腺癌中共同表达，金雀异黄素的两个作用能够增强曲妥珠单抗的抗癌作用。在这项体外研究中，我们测试了染料木黄酮与曲妥珠单抗的联合疗法是否对乳腺癌细胞表现出增强的效果。HER2 过表达的乳腺癌细胞单独用金雀异黄素或者与曲妥珠单抗联合治疗。分析这种治疗方法对增殖及基因表达的作用。高剂量金雀异黄素（10 umol/L）的 治疗显著增强了曲妥珠单抗对 HER2 过表达，ERα/β 阳性 BT-474 乳腺癌细胞的生长抑制作用。使用低剂量的曲妥珠单抗进行联合治疗发挥了与标准剂量单一药物治疗类似的效果。与此相反的是，这种效应在 ERα-阴性 SK-BR-3 细胞中不存在。在与2，3-双(4-羟苯基)丙腈这种ERβ 受体激动剂联合治疗时得到了类似的结果。这两种药物的生长抑制作用均伴随着公认肿瘤抑制基因ERβ 变体，二氯气肟，及其组合增强的表达进一步提高了这种受体的mRNA 水平。总之，染料木黄酮显著增强了曲妥珠单抗对体外BT-474 乳腺癌细胞的抗癌效果。这些数据特别是妇女 HER-2 的过表达和 ERα/β-阳性乳腺癌的相关性需要在动物或临床研究中验证。