Dextran-Catechin: An anticancer chemically-modified natural compound targeting copper that attenuates neuroblastoma growth
Autor: | Cyrille Boyer, Hien T. T. Duong, Murray D. Norris, Claudia Fleming, Orazio Vittorio, Katharina Gaus, Eugene Yee, Giuseppe Cirillo, Naresh Kumar, Michelle Haber, Elizabeth Hinde, Miriam Brandl, Maria Kavallaris, Kathleen Kimpton |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Antioxidant Cell Survival medicine.medical_treatment Antineoplastic Agents medicine.disease_cause Catechin Mice Neuroblastoma 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine copper transporter In vivo Animals Humans childhood cancer Medicine Cation Transport Proteins Copper Transporter 1 Mice Inbred BALB C business.industry Dextrans Glutathione medicine.disease Pediatric cancer 3. Good health Oxidative Stress 030104 developmental biology Oncology chemistry Mechanism of action 030220 oncology & carcinogenesis Immunology Cancer research Female copper metabolism medicine.symptom business Copper Intracellular Oxidative stress Research Paper |
Zdroj: | Oncotarget |
ISSN: | 1949-2553 |
Popis: | 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. |
Databáze: | OpenAIRE |
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