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Disulfiram-induced cytotoxicity and endo-lysosomal sequestration of zinc in breast cancer cells

Wiggins, Helen, Wymant, Jennifer, Solfa, Francesca, Hiscox, Stephen Edward, Taylor, Kathryn Mary, Westwell, Andrew David and Jones, Arwyn Tomos 2015. Disulfiram-induced cytotoxicity and endo-lysosomal sequestration of zinc in breast cancer cells. Biochemical Pharmacology 93 (3) , pp. 332-342. 10.1016/j.bcp.2014.12.014

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Abstract

Disulfiram, a clinically used alcohol-deterrent has gained prominence as a potential anti-cancer agent due to its impact on copper-dependent processes. Few studies have investigated zinc effects on disulfiram action, despite it having high affinity for this metal. Here we studied the cytotoxic effects of disulfiram in breast cancer cells, and its relationship with both intra and extracellular zinc. MCF-7 and BT474 cancer cell lines gave a striking time-dependent biphasic cytotoxic response between 0.01 and 10 μM disulfiram. Co-incubation of disulfiram with low-level zinc removed this effect, suggesting that availability of extracellular zinc significantly influences disulfiram efficacy. Live-cell confocal microscopy using fluorescent endocytic probes and the zinc dye Fluozin-3 revealed that disulfiram selectively and rapidly increased zinc levels in endo-lysosomes. Disulfiram also caused spatial disorganization of late endosomes and lysosomes, suggesting they are novel targets for this drug. This relationship between disulfiram toxicity and ionophore activity was consolidated via synthesis of a new disulfiram analog and overall we demonstrate a novel mechanism of disulfiram-cytotoxicity with significant clinical implications for future use as a cancer therapeutic.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
Publisher: Elsevier
ISSN: 0006-2952
Funders: Cancer Research UK
Related URLs:
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 23 December 2014
Last Modified: 21 Nov 2017 21:05
URI: http://orca-mwe.cf.ac.uk/id/eprint/69302

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