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In vitro and in vivo investigation of the anticancer activity and molecular mechanisms of disulfiram in non-small cell lung cancer
Butcher, Kate
Butcher, Kate
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2019-07
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Background: This study aims to repurpose disulfiram (DS), a drug used to treat alcohol dependence, into an effective treatment for non-small cell lung cancer (NSCLC). Lung cancer is the leading cause of cancer related death worldwide because of early metastasis and chemoresistance. Cancer stem cells (CSCs) play a key role in chemoresistance and metastasis. Our previous studies indicate that tumour hypoxia induced activation of the nuclear factor-κB (NF-κB) pathway; a pivotal regulator of CSCs. Therefore, development of an NF-κB and CSC targeting drug will improve NSCLC therapeutic outcomes. New drug development is an expensive and time-consuming procedure. DS demonstrates excellent in vitro anti-CSC activity in a wide range of cancers. Cytotoxicity of DS is copper (II) (Cu)-dependent. DS/Cu induces reactive oxygen species and inhibits NF-κB activity, leading cancer cells into apoptosis. The clinical application of DS as an anticancer drug is impeded by its very short half-life in the bloodstream (<2 minutes). To improve the drug delivery efficiency, we developed a poly lactic-co-glycolic formulation of DS (DS-PLGA), which demonstrates strong anti-cancer efficacy in NSCLC xenograft mouse models. Results: Spheroid and hypoxic cultured cells expressed high levels of CSC markers and were resistant to first- and second-line NSCLC anticancer drugs (doxorubicin, oxaliplatin, paclitaxel and gemcitabine). High NF-κB expression was detected in spheroid and hypoxia cultured NSCLC cell lines. After transfection with p65 subunit of NF-κB, A549 cells expressed CSC markers and became resistant to a wide range of anticancer drugs. DS (5-10 nM) supplemented with Cu (10 μM) induced cytotoxicity to hypoxic cultured NSCLC cells, DS (1 μM) in combination with Cu inhibited sphere reformation. DS/Cu effectively inhibited NF-κB activity, abolished the CSC population and was shown to synergistically enhance the cytotoxicity of the above conventional anti-NSCLC drugs with combination index (CI) values less than 1. The study also shows that protection of the thiuram structure of DS is vital for its cytotoxicity and DS-PLGA extends the half-life of free DS in the bloodstream from 2 minutes to 7 hours. Intravenous injection of DS-PLGA in combination with oral Cu can effectively target NSCLC xenografts in orthotopic and subcutaneous mouse models. Conclusion: DS/Cu specifically inhibits NF-κB pathway and targets CSCs in NSCLC cell lines. PLGA encapsulation improves delivery of DS which demonstrated very strong anticancer activity in NSCLC xenografts in vivo.
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Thesis or dissertation
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en
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A thesis submitted in partial fulfilment of the requirement of the University of Wolverhampton for the degree of Doctor of Philosophy.
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The University of Wolverhampton
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Attribution-NonCommercial-NoDerivatives 4.0 International