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dc.contributor.authorButcher, K
dc.contributor.authorKannappan, V
dc.contributor.authorKilari, RS
dc.contributor.authorMorris, MR
dc.contributor.authorMcConville, C
dc.contributor.authorArmesilla, AL
dc.contributor.authorWang, W
dc.date.accessioned2019-07-12T10:46:53Z
dc.date.available2019-07-12T10:46:53Z
dc.date.issued2018-07-21
dc.identifier.citationButcher, K., Kannappan, V., Kilari, R. S., Morris, M. R., McConville, C., Armesilla, A. L. and Wang, W. (2018)Investigation of the key chemical structures involved in the anticancer activity of disulfiram in A549 non-small cell lung cancer cell line, BMC Cancer (2018), 18:753.en
dc.identifier.pmid30031402
dc.identifier.doi10.1186/s12885-018-4617-xen
dc.identifier.urihttp://hdl.handle.net/2436/622546
dc.description.abstract© 2018 The Author(s). Background: Disulfiram (DS), an antialcoholism medicine, demonstrated strong anticancer activity in the laboratory but did not show promising results in clinical trials. The anticancer activity of DS is copper dependent. The reaction of DS and copper generates reactive oxygen species (ROS). After oral administration in the clinic, DS is enriched and quickly metabolised in the liver. The associated change of chemical structure may make the metabolites of DS lose its copper-chelating ability and disable their anticancer activity. The anticancer chemical structure of DS is still largely unknown. Elucidation of the relationship between the key chemical structure of DS and its anticancer activity will enable us to modify DS and speed its translation into cancer therapeutics. Methods: The cytotoxicity, extracellular ROS activity, apoptotic effect of DS, DDC and their analogues on cancer cells and cancer stem cells were examined in vitro by MTT assay, western blot, extracellular ROS assay and sphere-reforming assay. Results: Intact thiol groups are essential for the in vitro cytotoxicity of DS. S-methylated diethyldithiocarbamate (S-Me-DDC), one of the major metabolites of DS in liver, completely lost its in vitro anticancer activity. In vitro cytotoxicity of DS was also abolished when its thiuram structure was destroyed. In contrast, modification of the ethyl groups in DS had no significant influence on its anticancer activity. Conclusions: The thiol groups and thiuram structure are indispensable for the anticancer activity of DS. The liver enrichment and metabolism may be the major obstruction for application of DS in cancer treatment. A delivery system to protect the thiol groups and development of novel soluble copper-DDC compound may pave the path for translation of DS into cancer therapeutics.en
dc.description.sponsorshipThis work was supported by grant from British Lung Foundation (RG14–8) and Innovate UK (104022).en
dc.formatapplication/PDFen
dc.languageeng
dc.language.isoenen
dc.publisherSpringer Natureen
dc.relation.urlhttps://bmccancer.biomedcentral.com/articles/10.1186/s12885-018-4617-xen
dc.rightsLicence for published version: Creative Commons Attribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectHumansen
dc.subjectCopperen
dc.subjectReactive Oxygen Speciesen
dc.subjectDitiocarben
dc.subjectDisulfiramen
dc.subjectSulfhydryl Compoundsen
dc.subjectAntineoplastic Agentsen
dc.subjectStructure-Activity Relationshipen
dc.subjectNeoplastic Stem Cellsen
dc.subjectA549 Cellsen
dc.titleInvestigation of the key chemical structures involved in the anticancer activity of disulfiram in A549 non-small cell lung cancer cell lineen
dc.typeJournal articleen
dc.identifier.eissn1471-2407
dc.identifier.journalBMC Canceren
dc.date.updated2019-06-24T15:37:41Z
dc.contributor.institutionFaculty of Science & Engineering, University of Wolverhampton, Wolverhampton, WV1 1LY, UK.
pubs.place-of-publicationEngland
dc.date.accepted2018-06-20
rioxxterms.funderUniversity of Wolverhamptonen
rioxxterms.identifier.projectRG14-8en
rioxxterms.identifier.project104022en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2019-07-12en
dc.source.volume18
dc.source.issue1
dc.source.beginpage753
dc.description.versionPublished version
refterms.dateFCD2019-07-12T10:46:43Z
refterms.versionFCDVoR
refterms.dateFOA2019-07-12T10:46:53Z


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Licence for published version: Creative Commons Attribution 4.0 International
Except where otherwise noted, this item's license is described as Licence for published version: Creative Commons Attribution 4.0 International