Targeting copper metabolism in neuroblastoma using Dextran-Catechin — ASN Events
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Targeting copper metabolism in neuroblastoma using Dextran-Catechin (#157)

Orazio Vittorio 1 , Miriam Brandl , Giuseppe Cirillo 2 , KathleenKat Kimpton 1 , Elizabeth Hinde 3 , Hien Duong 4 , Cyrille Boyer 4 , Maria Kavallaris 1
  1. Children's Cancer Institute, Randwick, NSW, Australia
  2. University of Calabria, Catanzaro, Italy
  3. ARC Centre of Excellence in Advanced Molecular Imaging University of New South Wales, Sydney, Australia
  4. School of Chemical Engineering, UNSW Australia, Sydney, Australia

Background: Neuroblastoma is the second most common solid tumour in childhood and it is poorly responsive to therapy. Improved therapies are urgently required. Natural antioxidants, such as Catechin, showed anticancer properties with low toxicity to normal cells. However, their low stability in serum limits their use in clinical practice. We developed a novel modified form of Catechin linked to Dextran (Dext-Cat) to increase the stability of this antioxidant and investigated its anti-tumor efficacy and mechanism of action inneuroblastoma.

Material and Methods: Dext-Cat activity was tested using cell viability assays in four independent neuroblastoma cell lines. Intracellular metal ion content was measured by spectrophotometric analysis. Real time PCR was used for gene and western blotting for protein expression studies. Induction of oxidative stress was determined by NADH/NAD+ ratio using fluorescence-lifetime-imaging microscopy. Levels of GSH were examined by a colorimetric assay. Tumour growth in a xenograft neuroblastoma model was measured using calipers.

Results: The neuroblastoma cell lines IMR-32, BE(2)C and doxorubicin-resistant-BE(2)C-ADR were sensitive to Dext-Cat (IC50 17.83 µg/ml, 35.38 µg/ml and 31.47 µg/ml, respectively). Furthermore, doses of Dext-Cat up to 60 µg/ml did not affect viability in non-malignant cells, MRC-5. Cisplatin-resistant neuroblastoma cells (IMR-32-CisRes) exhibited 50% lower expression of copper transporter-1, which regulates Cisplatin uptake, and lower intracellular copper content compared to the parental cells. Importantly, these cells were 2.5-fold more resistant against Dext-Cat compared to the parental IMR-32 cells. We showed for the first time that Dext-Cat reacts with Copper generating reactive oxygen species and inducing cancer cell death. The decrease of NADH/NAD+ ratio and GSH level after Dext-Cat treatment confirmed the oxidative stress. Furthermore, Dext-Cat significantly reduced tumour growth in a xenograft neuroblastoma model, without affecting healthy tissues. 

Conclusion: Dextran-Catechin mediates its effects via copper metabolism and has the potential to be used as an effective therapy for aggressive neuroblastoma.