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dc.contributor.authorRahman, Mohummad Aminuren_US
dc.contributor.authorGras Navarro, Andreaen_US
dc.contributor.authorBrekke, Jorunnen_US
dc.contributor.authorEngelsen, Agneteen_US
dc.contributor.authorBindesbøll, Christianen_US
dc.contributor.authorSarowar, Shahinen_US
dc.contributor.authorBahador, Marziehen_US
dc.contributor.authorBifulco, Ersiliaen_US
dc.contributor.authorGoplen, Dorotaen_US
dc.contributor.authorWaha, Andreasen_US
dc.contributor.authorLie, Stein Atleen_US
dc.contributor.authorGjertsen, Bjørn Toreen_US
dc.contributor.authorSelheim, Frodeen_US
dc.contributor.authorEnger, Per Øyvinden_US
dc.contributor.authorSimonsen, Anneen_US
dc.contributor.authorEnger, Martha Chekenyaen_US
dc.PublishedRahman, Gras Navarro A, Brekke, Engelsen, Bindesbøll, Sarowar, Bahador, Bifulco, Goplen, Waha, Lie, Gjertsen, Selheim, Enger, Simonsen, Enger. Bortezomib administered prior to temozolomide depletes MGMT, chemosensitizes glioblastoma with unmethylated MGMT promoter and prolongs animal survival. British Journal of Cancer. 2019;121:545-555eng
dc.description.abstractBackground Resistance to temozolomide (TMZ) is due in part to enhanced DNA repair mediated by high expression of O6-methyl guanine DNA methyltransferase (MGMT) that is often characterised by unmethylated promoter. Here, we investigated pre-treatment of glioblastoma (GBM) cells with the 26S-proteasome inhibitor bortezomib (BTZ) as a strategy to interfere with MGMT expression and thus sensitise them to TMZ. Methods Cell lines and patient GBM-derived cells were examined in vitro, and the latter also implanted orthotopically into NOD-SCID C.B.-Igh-1b/lcrTac-Prkdc mice to assess efficacy and tolerability of BTZ and TMZ combination therapy. MGMT promoter methylation was determined using pyrosequencing and PCR, protein signalling utilised western blotting while drug biodistribution was examined by LC-MS/MS. Statistical analysis utilised Analysis of variance and the Kaplan–Meier method. Results Pre-treatment with BTZ prior to temozolomide killed chemoresistant GBM cells with unmethylated MGMT promoter through MGMT mRNA and protein depletion in vitro without affecting methylation. Chymotryptic activity was abolished, processing of NFkB/p65 to activated forms was reduced and corresponded with low MGMT levels. BTZ crossed the blood–brain barrier, diminished proteasome activity and significantly prolonged animal survival. Conclusion BTZ chemosensitized resistant GBM cells, and the schedule may be amenable for temozolomide refractory patients with unmethylated MGMT promoter.en_US
dc.publisherSpringer Natureeng
dc.rightsAttribution CC BYeng
dc.subjectCNS cancereng
dc.subjectTargeted therapieseng
dc.titleBortezomib administered prior to temozolomide depletes MGMT, chemosensitizes glioblastoma with unmethylated MGMT promoter and prolongs animal survivalen_US
dc.typePeer reviewed
dc.typeJournal article
dc.rights.holderCopyright 2019 The Author(s)
dc.source.journalBritish Journal of Cancer
dc.relation.projectNorges forskningsråd: 230691
dc.relation.projectNorges forskningsråd: 221831
dc.relation.projectNorges forskningsråd: 262652

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