School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
Sci Rep. 2017 Aug 9;7(1):7638. doi: 10.1038/s41598-017-07452-w.
Formation of blood vessels, or angiogenesis, is crucial to cancer progression. Thus, inhibiting angiogenesis can limit the growth and spread of tumors. The natural polyphenol catechin has moderate anti-tumor activity and interacts with copper, which is essential for angiogenesis. Catechin is easily metabolized in the body and this limits its clinical application. We have recently shown that conjugation of catechin with dextran (Dextran-Catechin) improves its serum stability, and exhibits potent anti-tumor activity against neuroblastoma by targeting copper homeostasis. Herein, we investigated the antiangiogenic activity of Dextran-Catechin and its mechanism. We found that Dextran-Catechin displayed potent antiangiogenic activity in vitro and in vivo. We demonstrated Dextran-Catechin generates reactive oxygen species which in turns disrupts copper homeostasis by depleting the copper importer CTR-1 and copper trafficking ATOX-1 protein. Mechanistically, we showed that disrupting copper homeostasis by knockdown of either CTR-1 or ATOX-1 protein can inhibit angiogenesis in endothelial cells. This data strongly suggests the Dextran-Catechin potent antiangiogenic activity is mediated by disrupting copper homeostasis. Thus, compounds such as Dextran-Catechin that affects both tumor growth and angiogenesis could lead the way for development of new drugs against high copper levels tumors.
血管生成，即血管的形成，对癌症的进展至关重要。因此，抑制血管生成可以限制肿瘤的生长和扩散。天然多酚儿茶素有适度的抗肿瘤活性，并与铜相互作用，铜是血管生成所必需的。儿茶素在体内易代谢，这限制了其临床应用。我们最近表明，儿茶素与葡聚糖（葡聚糖-儿茶素）缀合可以提高其血清稳定性，并通过靶向铜稳态来发挥针对神经母细胞瘤的强大抗肿瘤活性。在此，我们研究了葡聚糖-儿茶素的抗血管生成活性及其机制。我们发现葡聚糖-儿茶素在体外和体内均显示出强大的抗血管生成活性。我们证明葡聚糖-儿茶素会产生活性氧，通过耗尽铜摄取蛋白 CTR-1 和铜转运蛋白 ATOX-1 来破坏铜稳态。在机制上，我们表明通过敲低 CTR-1 或 ATOX-1 蛋白破坏铜稳态可以抑制内皮细胞中的血管生成。这一数据强烈表明，葡聚糖-儿茶素的强大抗血管生成活性是通过破坏铜稳态介导的。因此，像葡聚糖-儿茶素这样既能影响肿瘤生长又能影响血管生成的化合物，可能为开发针对高铜水平肿瘤的新药开辟道路。
