Cell cycle specific radiosensitisation by the disulfiram and copper complex
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Mathias Tesson1, Giorgio Anselmi2, Caitlin Bell3 and Robert Mairs1
1Radiation Oncology, Institute of Cancer Sciences, Wolfson Wohl Translational Cancer Research Center, University of Glasgow, Bearsden, Glasgow, UK
2Centre for Molecular and Cellular Biology of Inflammation, Peter Gorer Department of Immunobiology, Division of Immunology, Infection and Inflammatory Diseases, King’s College London, London, UK
3Cancer Research UK Beatson Institute, Bearsden, Glasgow, UK
Mathias Tesson, email: [email protected]
Keywords: disulfiram, copper, radiosensitisation, DNA replication, gemcitabine
Received: November 09, 2016 Accepted: June 29, 2017 Published: July 25, 2017
The disulfiram and copper complex (DSF:Cu) has emerged as a potent radiosensitising anti-cancer agent. The ability of copper to stabilise DSF in a planar conformation and to inhibit DNA replication enzymes stimulated our investigation of the effect of DSF:Cu on cell cycle regulation. Flow cytometry and immunoblotting were used to assess the effect of DSF:Cu on cell cycle progression of the neuroblastoma cell line SK-N-BE(2c) and the glioma cell line UVW. Treatment with 0.1 and 0.3 μM DSF:Cu inhibited DNA synthesis in SK-N-BE(2c) and UVW cells, respectively. The increased potency of ionising radiation treatment induced by DSF:Cu and/or gemcitabine was determined by clonogenic assay. Treatment with 0.3 μM DSF:Cu resulted in greater radiation kill, exemplified by dose enhancement factor values of 2.64 and 2.84 in SK-N-BE(2c) and UVW cells, respectively. Although DSF:Cu failed to sensitise S phase cells to irradiation, we observed that DSF:Cu radiosensitisation was potentiated by the S phase-specific cytotoxic drug gemcitabine. The efficacy of the combination treatment consisting of DSF:Cu, gemcitabine and ionising radiation was schedule-dependent. Together, these results describe cell cycle specific radiosensitisation by DSF:Cu. The well-established toxicity profiles of DSF and gemcitabine should facilitate their evaluation as a combination treatment in patients undergoing radiotherapy.
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