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fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Wiggins, Helen
Languages: English
Types: Doctoral thesis
Subjects: RC0254, RM
Breast cancer is the second-leading cause of cancer related death in women and future therapies may involve the strategic use of previously developed drugs, which have established toxicity profiles and are often ex-patent. The alcohol-deterrent disulfiram has been proposed as an anti-cancer agent, based on its capacity to interact with copper-dependent processes. However, little has been done to determine the relationship between this drug and zinc, despite knowledge that disulfiram binds this metal and zinc levels are dysregulated in breast cancer. This thesis investigated whether zinc is an important factor when considering disulfiram efficacy as an anti-breast cancer agent.\ud Disulfiram was toxic to MCF-7 and BT474 breast cancer cell lines and produced a striking time-dependent biphasic toxicity response between 5-20 μM. Co-incubation of the drug with low-level zinc removed this effect, suggesting that the availability of extracellular zinc significantly influenced disulfiram efficacy. Structure-activity relationship studies with disulfiram analogues revealed the biphasic effect could be influenced by altering the size of chemical groups bound to the drug’s nitrogen atom.\ud Live-cell confocal microscopy using fluorescent endocytic probes and the zinc dye Fluozin-3, coupled with the development of a complimentary Fluozin-3 flow cytometry assay found that disulfiram rapidly increased zinc levels in breast cancer cells specifically in endo-lysosomes. This indicates that the\ud ii\ud cytotoxic effects of this drug may be due to acute zinc overload. Further investigation into disulfiram effects on lysosomes suggested that the drug disrupts lysosomal membranes and releases hydrolytic enzymes into the cytosol. Lysosomal membrane permeabilisation has been demonstrated to promote apoptosis and may be a mechanism to explain disulfiram cytotoxicity in breast cancer. This could have important clinical implications in situations of high intracellular zinc as seen in breast tumours, indicating that breast cancer cells may be more susceptible to the zinc ionophore action of disulfiram than non-cancer cells.

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