Dextran-Catechin: An anticancer chemically-modified natural compound targeting copper that attenuates neuroblastoma growth
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Orazio Vittorio1,2, Miriam Brandl1,2, Giuseppe Cirillo3, Kathleen Kimpton1, Elizabeth Hinde4, Katharina Gaus4, Eugene Yee5, Naresh Kumar5, Hien Duong6,7, Claudia Fleming1, Michelle Haber1, Murray Norris1,8, Cyrille Boyer6,7, Maria Kavallaris1,2
1Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, NSW, Australia
2Australian Centre for NanoMedicine and ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, UNSW Australia, Sydney, NSW, Australia
3Department of Pharmacy Health and Nutritional Science, University of Calabria Arcavacata di Rende, Arcavacata, Rende CS, Italy
4ARC Centre of Excellence in Advanced Molecular Imaging, UNSW Australia, Sydney, NSW, Australia
5School of Chemistry, UNSW Australia, Sydney, NSW, Australia
6School of Chemical Engineering, UNSW Australia, Sydney, NSW, Australia
7Australian Centre for NanoMedicine, UNSW Australia, Sydney, NSW, Australia
8University of New South Wales Centre for Childhood Cancer Research, UNSW Australia, Sydney, NSW, Australia
Maria Kavallaris, email: [email protected]
Orazio Vittorio, email: [email protected]
Keywords: catechin, copper transporter, copper metabolism, childhood cancer
Received: April 01, 2016 Accepted: June 09, 2016 Published: June 21, 2016
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.
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