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dc.contributor.authorO'Flaherty, L.*
dc.contributor.authorShnyder, Steven D.*
dc.contributor.authorCooper, Patricia A.*
dc.contributor.authorCross, S.J.*
dc.contributor.authorWakefield, J.G.*
dc.contributor.authorPardo, O.E.*
dc.contributor.authorSeckl, M.J.*
dc.contributor.authorTavare, J.M.*
dc.date.accessioned2019-05-03T15:22:40Z
dc.date.available2019-05-03T15:22:40Z
dc.date.issued2019-04-10
dc.identifier.citationO'Flaherty L, Shnyder SD, Cooper PA et al (2019) Tumor growth suppression using a combination of taxol-based therapy and GSK3 inhibition in non-small cell lung cancer. PLoS ONE. 14(4): e0214610.en_US
dc.identifier.urihttp://hdl.handle.net/10454/17021
dc.descriptionYesen_US
dc.description.abstractGlycogen synthase kinase-3 (GSK3) is over-expressed and hyperactivated in non-small cell lung carcinoma (NSCLC) and plays a role in ensuring the correct alignment of chromosomes on the metaphase plate during mitosis through regulation of microtubule stability. This makes the enzyme an attractive target for cancer therapy. We examined the effects of a selective cell-permeant GSK3 inhibitor (CHIR99021), used alone or in combination with paclitaxel, using an in vitro cell growth assay, a quantitative chromosome alignment assay, and a tumor xenograft model. CHIR99021 inhibits the growth of human H1975 and H1299 NSCLC cell lines in a synergistic manner with paclitaxel. CHIR99021 and paclitaxel promoted a synergistic defect in chromosomal alignment when compared to each compound administered as monotherapy. Furthermore, we corroborated our in vitro findings in a mouse tumor xenograft model. Our results demonstrate that a GSK3 inhibitor and paclitaxel act synergistically to inhibit the growth of NSCLC cells in vitro and in vivo via a mechanism that may involve converging modes of action on microtubule spindle stability and thus chromosomal alignment during metaphase. Our findings provide novel support for the use of the GSK3 inhibitor, CHIR99021, alongside taxol-based chemotherapy in the treatment of human lung cancer.en_US
dc.description.sponsorshipCancer Research UK Project Grant (C16929/A14402) and the Elizabeth Blackwell Institute, through its Wellcome Trust ISSF Award (105612/Z/14/Z). The Imperial NIHR/Biomedical Research Centre and the CR-UK/Dept of Health funded Imperial Experimental Cancer Medicine Centre.en_US
dc.language.isoenen_US
dc.relation.isreferencedbyhttps://doi.org/10.1371/journal.pone.0214610en_US
dc.rights© 2019 O’Flaherty et al. This is an Open Access article distributed under the terms of the Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0/)en_US
dc.subjectTumor growth suppressionen_US
dc.subjectGSK3 inhibitionen_US
dc.subjectTaxolen_US
dc.subjectNon-small cell lung carcinomaen_US
dc.subjectCancer therapyen_US
dc.titleTumor growth suppression using a combination of taxol-based therapy and GSK3 inhibition in non-small cell lung canceren_US
dc.status.refereedYesen_US
dc.date.Accepted2019-03-17
dc.typeArticleen_US
dc.type.versionPublished versionen_US
refterms.dateFOA2019-05-03T15:22:40Z


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