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dc.contributor.authorDanovi, Den
dc.contributor.authorFolarin, Aen
dc.contributor.authorGogolok, Sen
dc.contributor.authorEnder, Cen
dc.contributor.authorElbatsh, AMen
dc.contributor.authorEngström, PGen
dc.contributor.authorStricker, SHen
dc.contributor.authorGagrica, Sen
dc.contributor.authorGeorgian, Aen
dc.contributor.authorYu, Den
dc.contributor.authorU, KPen
dc.contributor.authorHarvey, KJen
dc.contributor.authorFerretti, Pen
dc.contributor.authorPaddison, PJen
dc.contributor.authorPreston, JEen
dc.contributor.authorAbbott, NJen
dc.contributor.authorBertone, Paulen
dc.contributor.authorSmith, Aen
dc.contributor.authorPollard, SMen
dc.date.accessioned2018-11-29T00:30:28Z
dc.date.available2018-11-29T00:30:28Z
dc.date.issued2013-10-30en
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286040
dc.description.abstractGlioblastoma multiforme (GBM) is the most common primary brain cancer in adults and there are few effective treatments. GBMs contain cells with molecular and cellular characteristics of neural stem cells that drive tumour growth. Here we compare responses of human glioblastoma-derived neural stem (GNS) cells and genetically normal neural stem (NS) cells to a panel of 160 small molecule kinase inhibitors. We used live-cell imaging and high content image analysis tools and identified JNJ-10198409 (J101) as an agent that induces mitotic arrest at prometaphase in GNS cells but not NS cells. Antibody microarrays and kinase profiling suggested that J101 responses are triggered by suppression of the active phosphorylated form of polo-like kinase 1 (Plk1) (phospho T210), with resultant spindle defects and arrest at prometaphase. We found that potent and specific Plk1 inhibitors already in clinical development (BI 2536, BI 6727 and GSK 461364) phenocopied J101 and were selective against GNS cells. Using a porcine brain endothelial cell blood-brain barrier model we also observed that these compounds exhibited greater blood-brain barrier permeability in vitro than J101. Our analysis of mouse mutant NS cells (INK4a/ARF(-/-), or p53(-/-)), as well as the acute genetic deletion of p53 from a conditional p53 floxed NS cell line, suggests that the sensitivity of GNS cells to BI 2536 or J101 may be explained by the lack of a p53-mediated compensatory pathway. Together these data indicate that GBM stem cells are acutely susceptible to proliferative disruption by Plk1 inhibitors and that such agents may have immediate therapeutic value.
dc.publisherPublic Library of Science (PLoS)
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleA high-content small molecule screen identifies sensitivity of glioblastoma stem cells to inhibition of polo-like kinase 1en
dc.typeArticle
prism.issueIdentifier10en
prism.numbere77053en
prism.publicationDate2013en
prism.publicationNamePLoS ONEen
prism.volume8en
dc.identifier.doi10.17863/CAM.33358
dcterms.dateAccepted2013-08-29en
rioxxterms.versionofrecord10.1371/journal.pone.0077053en
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2013-10-30en
dc.contributor.orcidBertone, Paul [0000-0001-5059-4829]
rioxxterms.typeJournal Article/Reviewen
cam.issuedOnline2013-10-30en


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International