Chk1 inhibition significantly potentiates activity of nucleoside analogs in TP53-mutated B-lymphoid cells

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dc.contributor.authorZemanová, Janacs
dc.contributor.authorHylse, Ondřejcs
dc.contributor.authorČolláková, Janacs
dc.contributor.authorVeselý, Pavelcs
dc.contributor.authorOltová, Alexandracs
dc.contributor.authorBorský, Marekcs
dc.contributor.authorZápražná, Kristínacs
dc.contributor.authorKašpárková, Mariecs
dc.contributor.authorJanovská, Pavlínacs
dc.contributor.authorVerner, Jancs
dc.contributor.authorKohoutek, Jiřícs
dc.contributor.authorDzimková, Martacs
dc.contributor.authorBryja, Vítězslavcs
dc.contributor.authorJašková, Zuzanacs
dc.contributor.authorBrychtová, Yvonacs
dc.contributor.authorParuch, Kamilcs
dc.contributor.authorTrbušek, Martincs
dc.coverage.issue38cs
dc.coverage.volume7cs
dc.date.accessioned2020-10-29T10:05:44Z
dc.date.available2020-10-29T10:05:44Z
dc.date.issued2016-08-19cs
dc.description.abstractTreatment options for TP53-mutated lymphoid tumors are very limited. In experimental models, TP53-mutated lymphomas were sensitive to direct inhibition of checkpoint kinase 1 (Chk1), a pivotal regulator of replication. We initially tested the potential of the highly specific Chk1 inhibitor SCH900776 to synergize with nucleoside analogs (NAs) fludarabine, cytarabine and gemcitabine in cell lines derived from B-cell malignancies. In p53-proficient NALM-6 cells, SCH900776 added to NAs enhanced signaling towards Chk1 (pSer317/pSer345), effectively blocked Chk1 activation (Ser296 autophosphorylation), increased replication stress (p53 and -H2AX accumulation) and temporarily potentiated apoptosis. In p53-defective MEC-1 cell line representing adverse chronic lymphocytic leukemia (CLL), Chk1 inhibition together with NAs led to enhanced and sustained replication stress and significantly potentiated apoptosis. Altogether, among 17 tested cell lines SCH900776 sensitized four of them to all three NAs. Focusing further on MEC-1 and co-treatment of SCH900776 with fludarabine, we disclosed chromosome pulverization in cells undergoing aberrant mitoses. SCH900776 also increased the effect of fludarabine in a proportion of primary CLL samples treated with pro-proliferative stimuli, including those with TP53 disruption. Finally, we observed a fludarabine potentiation by SCH900776 in a T-cell leukemia 1 (TCL1)-driven mouse model of CLL. Collectively, we have substantiated the significant potential of Chk1 inhibition in B-lymphoid cells.en
dc.formattextcs
dc.format.extent1-16cs
dc.format.mimetypeapplication/pdfcs
dc.identifier.citationOncotarget. 2016, vol. 7, issue 38, p. 1-16.en
dc.identifier.doi10.18632/oncotarget.11388cs
dc.identifier.issn1949-2553cs
dc.identifier.other127880cs
dc.identifier.urihttp://hdl.handle.net/11012/84152
dc.language.isoencs
dc.publisherImpact Journalscs
dc.relation.ispartofOncotargetcs
dc.relation.urihttp://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=11388cs
dc.rightsCreative Commons Attribution 3.0 Unportedcs
dc.rights.accessopenAccesscs
dc.rights.sherpahttp://www.sherpa.ac.uk/romeo/issn/1949-2553/cs
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/cs
dc.subjectkontrolní bod kinázy 1/Chk1
dc.subjectSCH900776
dc.subjectanalogy purinových nukleosidů
dc.subjectchronická lymfocytární leukemie
dc.subjectTP53
dc.subjectcheckpoint kinase 1/Chk1en
dc.subjectSCH900776en
dc.subjectnucleoside analogsen
dc.subjectchronic lymphocytic leukemiaen
dc.subjectTP53en
dc.titleChk1 inhibition significantly potentiates activity of nucleoside analogs in TP53-mutated B-lymphoid cellsen
dc.title.alternativeChk1 inhibice výrazně zvyšuje aktivitu nukleosidových analogů v TP53-mutovaných B-lymfoidních buněkcs
dc.type.driverarticleen
dc.type.statusPeer-revieweden
dc.type.versionpublishedVersionen
sync.item.dbidVAV-127880en
sync.item.dbtypeVAVen
sync.item.insts2020.10.29 11:05:44en
sync.item.modts2020.09.14 12:14:47en
thesis.grantorVysoké učení technické v Brně. Středoevropský technologický institut VUT. Experimentální biofotonikacs
thesis.grantorVysoké učení technické v Brně. Fakulta strojního inženýrství. Ústav fyzikálního inženýrstvícs
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