Abstract
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.
Highlights
The dithiocarbamate disulfiram (DSF) has been used for several decades as a deterrent in the treatment of alcohol addiction [1]
We report that disulfiram and copper complex (DSF):Cu treatment sensitised cancer cells to ionising radiation via a mechanism independent of proteasome activity
The effects of DSF:Cu on cell cycle progression were manifest by inhibition of DNA synthesis, CDK1 depletion and blockade of entry into mitosis
Summary
The dithiocarbamate disulfiram (DSF) has been used for several decades as a deterrent in the treatment of alcohol addiction [1]. DSF generates oxidative stress through the inhibition of NF-κB activation [7], by inhibition of superoxide dismutase (SOD) [8] and as a result of its induction of an increase in the ratio of oxidised glutathione to its reduced form [9]. Intracellular copper deposition could be cytotoxic through the generation of oxidative stress resulting from Fenton reactions [producing cupric ions and hydroxyl radicals] or through enzymatic inhibition by virtue of copper’s binding to peptidic bonds. Copper complexes have been shown to intercalate between the base pairs of DNA owing to their planar conformation [13,14,15] These reports raise the possibility that copper confers upon DSF a favourable conformation for DNA intercalation, resulting in alteration to the structure of DNA and cell death. It has been suggested that DSF and its reduced form, diethyldithiocarbamate, inhibit www.impactjournals.com/oncotarget
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
