title: 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.
authors.affiliation: 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.
authors.forename: Orazio
authors.initials: O
authors.lastname: Vittorio
authors.affiliation: 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.
authors.forename: Miriam
authors.initials: M
authors.lastname: Brandl
authors.affiliation: Department of Pharmacy Health and Nutritional Science, University of Calabria Arcavacata di Rende, Arcavacata, Rende CS, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirillo
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, NSW, Australia.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Kimpton
authors.affiliation: ARC Centre of Excellence in Advanced Molecular Imaging, UNSW Australia, Sydney, NSW, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hinde
authors.affiliation: ARC Centre of Excellence in Advanced Molecular Imaging, UNSW Australia, Sydney, NSW, Australia.
authors.forename: Katharina
authors.initials: K
authors.lastname: Gaus
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW, Australia.
authors.forename: Eugene
authors.initials: E
authors.lastname: Yee
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW, Australia.
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
authors.affiliation: School of Chemical Engineering, UNSW Australia, Sydney, NSW, Australia.|Australian Centre for NanoMedicine, UNSW Australia, Sydney, NSW, Australia.
authors.forename: Hien
authors.initials: H
authors.lastname: Duong
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, NSW, Australia.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fleming
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, NSW, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Haber
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, NSW, Australia.|University of New South Wales Centre for Childhood Cancer Research, UNSW Australia, Sydney, NSW, Australia.
authors.forename: Murray
authors.initials: M
authors.lastname: Norris
authors.affiliation: School of Chemical Engineering, UNSW Australia, Sydney, NSW, Australia.|Australian Centre for NanoMedicine, UNSW Australia, Sydney, NSW, Australia.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Boyer
authors.affiliation: 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.
authors.forename: Maria
authors.initials: M
authors.lastname: Kavallaris
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002392:Catechin / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000378:metabolism*; D000079923:Copper Transporter 1; D003911:Dextrans / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D003911:Dextrans; C490079:SLC31A1 protein, human; D003300:Copper; D002392:Catechin
keywords: catechin; childhood cancer; copper metabolism; copper transporter