{"id":{"repo_id":"wlv","oai_identifier":"oai:wlv.openrepository.com:2436/623026"},"canonical_url":"https://search.dev.ndltd.org/etd/wlv/oai:wlv.openrepository.com:2436/623026","repository":{"repo_id":"wlv","name":"University of Wolverhampton","base_url":"https://wlv.openrepository.com/server/oai/request"},"display":{"title":"In vitro and in vivo investigation of the anticancer activity and molecular mechanisms of disulfiram in non-small cell lung cancer","abstract":"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.","abstract_html":"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 (&lt;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.","abstract_has_math":false,"creators":["Butcher, Kate"],"institution":"University of Wolverhampton","degree_name":"PhD","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Wang, Weiguang"],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019-07","date_published":"2019-07","updated_at":"2026-07-24T06:09:29Z","subjects":["disulfiram","non-small cell lung cancer","chemoresistance","cancer stem cells","hypoxia","NF-κB"],"languages":[],"rights":["Attribution-NonCommercial-NoDerivatives 4.0 International"],"rights_urls":["https://wlv.dspace7.openrepository.com/bitstreams/61aa7228-f48c-4ccd-9304-c1ddaf343056/download"],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Wang, Weiguang"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["The University of Wolverhampton"]},{"key":"dc:creator","label":"Author","values":["Butcher, Kate"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2019-07"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Wolverhampton"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["http://hdl.handle.net/2436/623026"]},{"key":"dc:type","label":"Dc Type","values":["Thesis or dissertation"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["PhD"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["disulfiram","non-small cell lung cancer","chemoresistance","cancer stem cells","hypoxia","NF-κB"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["https://wlv.dspace7.openrepository.com/bitstreams/61aa7228-f48c-4ccd-9304-c1ddaf343056/download","Attribution-NonCommercial-NoDerivatives 4.0 International"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://wlv.dspace7.openrepository.com/bitstreams/76e7a689-e14c-42bf-80de-13d889c45e0d/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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."]},{"key":"dc:format.checksum.md5","label":"Dc Format Checksum Md5","values":["a7f571802114d659f5a5c82ecd0e8eaa","8a4605be74aa9ea9d79846c1fba20a33","82faa9540818fea2d6c499848ea85dab"]},{"key":"dc:title","label":"Title","values":["In vitro and in vivo investigation of the anticancer activity and molecular mechanisms of disulfiram in non-small cell lung cancer"]}]}],"canonical_facts":{"dc:contributor.advisor":["Wang, Weiguang"],"dc:contributor.sponsor":["The University of Wolverhampton"],"dc:creator":["Butcher, Kate"],"dc:date.issued":["2019-07"],"dc:description.abstract":["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."],"dc:format.checksum.md5":["a7f571802114d659f5a5c82ecd0e8eaa","8a4605be74aa9ea9d79846c1fba20a33","82faa9540818fea2d6c499848ea85dab"],"dc:identifier.uri":["https://wlv.dspace7.openrepository.com/bitstreams/76e7a689-e14c-42bf-80de-13d889c45e0d/download"],"dc:publisher.institution":["University of Wolverhampton"],"dc:relation.isreferencedby":["http://hdl.handle.net/2436/623026"],"dc:rights":["https://wlv.dspace7.openrepository.com/bitstreams/61aa7228-f48c-4ccd-9304-c1ddaf343056/download","Attribution-NonCommercial-NoDerivatives 4.0 International"],"dc:subject":["disulfiram","non-small cell lung cancer","chemoresistance","cancer stem cells","hypoxia","NF-κB"],"dc:title":["In vitro and in vivo investigation of the anticancer activity and molecular mechanisms of disulfiram in non-small cell lung cancer"],"dc:type":["Thesis or dissertation"],"dc:type.qualificationlevel":["Doctoral"],"dc:type.qualificationname":["PhD"]},"updated_at":"2026-07-24T06:09:29Z"}