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.
Highlights
Neuroblastoma is the third most common type of childhood cancer after leukemia and brain tumours
Results showed that BE(2)-C and IMR-32 cells had significantly higher intracellular copper levels compared to IMR-32CisRes and MRC-5 cells (Figure 2C). These results indicate that high expression levels of Copper transporter 1 (CTR1) are associated with high intracellular copper, which in turn correlates with the cytotoxic activity of Dextran-Catechin in neuroblastoma cells
We have shown that a conjugate of this natural component, Dextran-Catechin, with improved serum stability is effective against neuroblastoma cells
Summary
Neuroblastoma is the third most common type of childhood cancer after leukemia and brain tumours. Due to the toxic side effects of chemotherapy, survivors of neuroblastoma frequently have lifelong health issues from the therapy they received as a child [2]. Occurring antioxidants have shown anticancer properties and often display low toxicity to normal cells [3]. To overcome the stability issue, we adopted a previously described bio-compatible chemical synthetic strategy for the conjugation of catechin with dextran [9]. This new conjugate, named Dextran-Catechin, showed increased serum stability compared to catechin alone, and anticancer activity in pancreatic ductal adenocarcinoma cells in vitro [10]. Its broader effect in other aggressive cancers and drug resistant cells, as well as its mechanism of action are unknown
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