Vittorio Orazio, Brandl Miriam, Cirillo Giuseppe, Kimpton Kathleen, Hinde Elizabeth, Gaus Katharina, Yee Eugene, Kumar Naresh, Duong Hien, Fleming Claudia, Haber Michelle, Norris Murray, Boyer Cyrille, Kavallaris Maria
Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, NSW, Australia.
Australian Centre for NanoMedicine and ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, UNSW Australia, Sydney, NSW, Australia.
Oncotarget. 2016 Jul 26;7(30):47479-47493. doi: 10.18632/oncotarget.10201.
Neuroblastoma is frequently diagnosed at advanced stage disease and treatment includes high dose chemotherapy and surgery. Despite the use of aggressive therapy survival rates are poor and children that survive their disease experience long term side effects from their treatment, highlighting the need for effective and less toxic therapies. Catechin is a natural polyphenol with anti-cancer properties and limited side effects, however its mechanism of action is unknown. Here we report that Dextran-Catechin, a conjugated form of catechin that increases serum stability, is preferentially and markedly active against neuroblastoma cells having high levels of intracellular copper, without affecting non-malignant cells. Copper transporter 1 (CTR1) is the main transporter of copper in mammalian cells and it is upregulated in neuroblastoma. Functional studies showed that depletion of CTR1 expression reduced intracellular copper levels and led to a decrease in neuroblastoma cell sensitivity to Dextran-Catechin, implicating copper in the activity of this compound. Mechanistically, Dextran-Catechin was found to react with copper, inducing oxidative stress and decreasing glutathione levels, an intracellular antioxidant and regulator of copper homeostasis. In vivo, Dextran-Catechin significantly attenuated tumour growth in human xenograft and syngeneic models of neuroblastoma. Thus, Dextran-Catechin targets copper, inhibits tumour growth, and may be valuable in the treatment of aggressive neuroblastoma and other cancers dependent on copper for their growth.
神经母细胞瘤常于疾病晚期被诊断出来，其治疗包括大剂量化疗和手术。尽管采用了积极的治疗方法，但生存率仍很低，且存活下来的儿童会经历治疗带来的长期副作用，这凸显了对有效且毒性较小的治疗方法的需求。儿茶素是一种具有抗癌特性且副作用有限的天然多酚，但它的作用机制尚不清楚。在此我们报告，葡聚糖 - 儿茶素是儿茶素的一种共轭形式，可提高血清稳定性，它对细胞内铜含量高的神经母细胞瘤细胞具有优先且显著的活性，而不影响非恶性细胞。铜转运蛋白1（CTR1）是哺乳动物细胞中铜的主要转运体，在神经母细胞瘤中上调。功能研究表明，CTR1表达的缺失会降低细胞内铜水平，并导致神经母细胞瘤细胞对葡聚糖 - 儿茶素的敏感性降低，这表明铜与该化合物的活性有关。从机制上讲，发现葡聚糖 - 儿茶素与铜发生反应，诱导氧化应激并降低谷胱甘肽水平，谷胱甘肽是一种细胞内抗氧化剂和铜稳态调节剂。在体内，葡聚糖 - 儿茶素在人神经母细胞瘤异种移植和同基因模型中显著减弱肿瘤生长。因此，葡聚糖 - 儿茶素靶向铜，抑制肿瘤生长，可能对侵袭性神经母细胞瘤和其他依赖铜生长的癌症的治疗具有重要价值。
