Molecular Nutrition & Food Research, 2011, 55(4):553–559.

Soy isoflavone genistein induces cell death in breast cancer cells through mobilization of endogenous copper ions and generation of reactive oxygen species

Ahmad Aamir, Zhiwei Wang, et al

Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, India; and Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

SCOPE: Worldwide geographical variation in cancer incidence indicates a correlation between dietary habits and cancer risk. Epidemiological studies have suggested that populations with high isoflavone intake through soy consumption have lower rates of breast, prostate, and colon cancer. Isoflavone genistein in soybean is considered a potent chemopreventive agent against cancer. Although several mechanisms have been proposed, a clear anticancer action mechanism of genistein is still not known.

METHODS AND RESULTS: Here, we show that the cytotoxic action of genistein against breast cancer cells involves mobilization of endogenous copper. Further, whereas the copper specific chelator neocuproine is able to inhibit the apoptotic potential of genistein, the molecules which specifically bind iron (desferroxamine mesylate) and zinc (histidine) are relatively ineffective in causing such inhibition. Also, genistein-induced apoptosis in these cells is inhibited by scavengers of reactive oxygen species (ROS) implicating ROS as effector elements leading to cell death.

CONCLUSIONS: As copper levels are known to be considerably elevated in almost all types of cancers, in this proof-of-concept study we show that genistein is able to target endogenous copper leading to prooxidant signaling and consequent cell death. We believe that such a mechanism explains the anticancer effect of genistein as also its preferential cytotoxicity towards cancer cells.

德国《分子营养与食品研究》，2011年4月

在乳腺癌细胞中大豆异黄酮金雀异黄素通过调动内源性铜离子和活性氧的生成诱导细胞死亡

艾哈迈德 阿米尔，王志伟等

印度阿拉伯马格里布联盟生命科学院生化系，美国韦恩州医科大学卡尔诺斯癌症研究所病理系

目标︰ 癌症的发病率在世界范围内的地理差异表明饮食习惯与癌症风险之间的相关性。流行病学研究表明，通过食用大豆保持高异黄酮摄取量的人群患乳腺癌、 前列腺癌和结肠癌的几率更低。大豆中的异黄酮金雀异黄素被认为是一种强效的化学抗癌制剂。虽然已经提出了几种机制，染料木黄酮明确的抗癌作用机理目前尚不清楚。

方法和结果︰ 在这里，我们展示了金雀异黄素对乳腺癌细胞的细胞毒害作用并涉及到内源性铜的运用。此外，尽管铜的特定螯合剂10-菲罗啉能够抑制染料木黄酮的细胞凋亡作用，专门结合铁 （去铁乙胺甲磺酸） 和锌 （组氨酸）的分子对造成这种抑制作用相对无效。而且，在这些细胞中染料木黄酮诱导的细胞凋亡被活性氧 (ROS)的清除剂抑制，其中 ROS 作为效应器成分会导致细胞死亡。

结论︰ 因为在几乎所有类型的癌症中已知铜的浓度被大幅度提升，在这项概念验证研究中我们表明那金雀异黄素能够靶向内源性铜导致促氧化信号，随后细胞死亡。我们相信这种机制阐明了染料木黄酮的抗癌作用及其对癌症细胞的毒害优先权。