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DIVERSet JAG compounds inhibit topoisomerase II and are effective against adult and pediatric high-grade gliomas

2019Journal article Open access
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dc.contributor.authorHowarth, Alison
dc.contributor.authorSimms, Claire
dc.contributor.authorKerai, Nitesh
dc.contributor.authorAllen, Olivia
dc.contributor.authorMihajluk, Karina
dc.contributor.authorMadureira, Patricia
dc.contributor.authorSokratous, Giannis
dc.contributor.authorCragg, Simon
dc.contributor.authorLee, Sang Y.
dc.contributor.authorMorley, Andy D.
dc.contributor.authorAshkan, Keyoumars
dc.contributor.authorCox, Paul A.
dc.contributor.authorPilkington, Geoffrey J.
dc.contributor.authorHill, Richard
dc.date.accessioned2020-02-05T13:39:35Z
dc.date.available2020-02-05T13:39:35Z
dc.date.issued2019
dc.description.abstractHigh-grade gliomas (HGGs) are aggressive primary brain tumors with local invasive growth and poor clinical prognosis in both adult and pediatric patients. Clinical response is compounded by resistance to standard frontline antineoplastic agents, an absence of novel therapeutics, and poor in vitro models to evaluate these. We screened a range of recently identified anticancer compounds in conventional adult, pediatric, and new biopsy-derived HGG models. These in vitro lines showed a range of sensitivity to standard chemotherapeutics, with varying expression levels of the prognostic markers hypoxia-induced factor (HIF) 1α and p53. Our evaluation of lead DIVERSet library compounds identified that JAG-6A, a compound that was significantly more potent than temozolomide or etoposide, was effective against HGG models in two-dimensional and three-dimensional systems; mediated this response by the potent inhibition of topoisomerase Iiα; remained effective under normoxic and hypoxic conditions; and displayed limited toxicity to non-neoplastic astrocytes. These data suggest that JAG-6A could be an alternative topoisomerase IIα inhibitor and used for the treatment of HGG.pt_PT
dc.description.sponsorshipFunding Agency Brain Tumour Research Ollie Young Foundation Portuguese Foundation for Science and Technology IF/00614/2014 FCT exploratory grant IF/00614/2014/CP12340006 FCT Research Center Grant UID/BIM/04773/2013CBMR1334pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1016/j.tranon.2019.07.007pt_PT
dc.identifier.issn1936-5233
dc.identifier.urihttp://hdl.handle.net/10400.1/13459
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectBrain-stem gliomapt_PT
dc.subjectVincristine chemotherapypt_PT
dc.titleDIVERSet JAG compounds inhibit topoisomerase II and are effective against adult and pediatric high-grade gliomaspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage1385pt_PT
oaire.citation.issue10pt_PT
oaire.citation.startPage1375pt_PT
oaire.citation.titleTranslational Oncologypt_PT
oaire.citation.volume12pt_PT
person.familyNameMadureira
person.familyNameHill
person.givenNamePatricia
person.givenNameRichard
person.identifier.ciencia-id6612-9A86-6929
person.identifier.orcid0000-0002-4856-3908
person.identifier.orcid0000-0003-0394-6048
person.identifier.scopus-author-id10340140500
person.identifier.scopus-author-id55266604200
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicationa40de6a3-d52d-45dd-8620-cb94a22ebc8f
relation.isAuthorOfPublicatione67f4a4f-aa35-4740-87b0-0cd07a9e1993
relation.isAuthorOfPublication.latestForDiscoverya40de6a3-d52d-45dd-8620-cb94a22ebc8f

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