In vitro and in vivo investigation of the anticancer activity and molecular mechanisms of disulfiram in non-small cell lung cancer
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AbstractBackground: 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.
PublisherUniversity of Wolverhampton
TypeThesis or dissertation
DescriptionA thesis submitted in partial fulfilment of the requirement of the University of Wolverhampton for the degree of Doctor of Philosophy.
SponsorsThe University of Wolverhampton
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