Dextran-Catechin: An anticancer chemically-modified natural compound targeting copper that attenuates neuroblastoma growth

Abstract

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.

Dextran-Catechin inhibits angiogenesis by disrupting copper homeostasis in endothelial cells

“…The finding in the in vivo model of neuroblastoma showing reduction in the number of vascular structures when they were treated with Dextran-Catechin furthers supports the anti-angiogenic effects of Dextran-Catechin reported in the in vitro experiments. The results from this study, combined with our previous study on Dextran-Catechin 18 , suggest that Dextran-Catechin exerts its anticancer and antiangiogenic properties by targeting copper homeostasis in tumor and endothelial cells. Furthermore, Dextran-Catechin also has minimal effect on the viability of non-malignant MRC-5 cells 18 , making it highly attractive as an anti-tumor agent with multiple modes of action.…”

“…We recently demonstrated that Dextran-Catechin can disrupt copper metabolism in cancer cells 18 . Therefore, we postulated that a possible antiangiogenic mechanism of Dextran-Catechin is through the disruption the copper homeostasis in endothelial cells.…”

“…To determine the in vivo anti-angiogenic activity of Dextran-Catechin, we investigated the response of formation of blood vessels in a human neuroblastoma xenograft model 18 . After the 26 day experimental period, tumor slices were stained for CD31 protein, which indicates the presence of endothelial cells.…”

“…Natural derived polyphenols, such as catechin, have anticancer and antiangiogenic activity but their low bioavailability has limited their clinical applications 15 – 17 . We have previously shown that the conjugation of Catechin with Dextran, here referred to as Dextran-Catechin, has led to higher serum stability and exhibits potent anti-tumor properties by targeting copper homeostasis in neuroblastoma 18 .…”

Copper as the Target for Anticancer Nanomedicine

“…[127,128] Based on the high binding affinity between sulfur and copper ions, Zheng et al developed sulfur nanoparticles (Nano-S) as Cu chelators to inhibit the growth of cancer cells. [131,132] We developed a terminal-PEGylated polyacylthiourea dendrimer (PATU-PEG; Figure 5a) through sequential click couplings of orthogonal monomers. Moreover, cells pretreated with Nano-S showed much higher Ctr1 expression and significantly elevated cellular uptake of cisplatin, in comparison with control cells.…”