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Selective Delivery of Copper Enhances Cytotoxicity of Millimolar Concentrations of Ascorbate towards Cancer Cells
Author(s) -
Michels Alexander,
Yu David,
Frei Balz
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.263.3
Subject(s) - ascorbic acid , chemistry , cytotoxicity , molar concentration , cancer cell , sodium ascorbate , pro oxidant , hydrogen peroxide , cell culture , in vivo , biochemistry , mcf 7 , intracellular , antioxidant , in vitro , cancer , biology , organic chemistry , human breast , food science , microbiology and biotechnology , genetics
Millimolar concentrations of ascorbic acid (millimolar ascorbate) in cell culture media and biological fluids may cause the generation of hydrogen peroxide (H 2 O 2 )via ascorbate auto‐oxidation and reduction of molecular oxygen. Although many cancer cell lines appear to be particularly susceptible to H 2 O 2 exposure , the cytotoxicity of millimolar ascorbate may also be observed in normal cell lines. Delivery of redox‐active copper specifically to cancer cells, but not normal cells, may increase the cancer cells' susceptibility to killing by H 2 O 2 due to increased intracellular production of hydroxyl radicals and oxidative DNA damage. Consistent with this hypothesis, we observed that pre‐treatment of colon cancer cells (Hct 116 or HT29) with the clinically‐used copper compound, copper(II)‐diacetyl‐bis‐methylthiosemicarbazone (CuATSM), increased the cytotoxic effects of millimolar ascorbate as measured by MTT and luciferase‐based methods. Since CuATSM does not increase the apparent rate of ascorbate oxidation in cell culture media, extracellular H 2 O 2 production is not increased. Rather, the cytotoxic effects of CuATSM treatment are due to the intracellular accumulation of copper ions. The addition of millimolar ascorbate or H 2 O 2 results in an acceleration of the copper‐mediated oxidative damage and cytotoxicity. The reduction of CuATSM and subsequent accumulation of copper is thought to be specific to cancer cells in culture and in vivo . Overall, our results suggest that CuATSM may be used in vivo to deliver redox‐active copper to cancer cells, thereby increasing the efficacy of intravenous administration of ascorbic acid as a cancer therapy.