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

Identifikátory výsledku

  • Kód výsledku v IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F16%3A00506414" target="_blank" >RIV/68081707:_____/16:00506414 - isvavai.cz</a>

  • Nalezeny alternativní kódy

    RIV/00159816:_____/16:00065981 RIV/00216224:14310/16:00088918 RIV/00216305:26620/16:PU120162 RIV/00027162:_____/16:N0000035 RIV/65269705:_____/16:00065981

  • Výsledek na webu

    <a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=11388&path%5B%5D=36488" target="_blank" >http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=11388&path%5B%5D=36488</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.18632/oncotarget.11388" target="_blank" >10.18632/oncotarget.11388</a>

Alternativní jazyky

  • Jazyk výsledku

    angličtina

  • Název v původním jazyce

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

  • Popis výsledku v původním jazyce

    Treatment 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 eta-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.

  • Název v anglickém jazyce

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

  • Popis výsledku anglicky

    Treatment 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 eta-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.

Klasifikace

  • Druh

    J<sub>imp</sub> - Článek v periodiku v databázi Web of Science

  • CEP obor

  • OECD FORD obor

    10601 - Cell biology

Návaznosti výsledku

  • Projekt

  • Návaznosti

    I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Ostatní

  • Rok uplatnění

    2016

  • Kód důvěrnosti údajů

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Údaje specifické pro druh výsledku

  • Název periodika

    OncoTarget

  • ISSN

    1949-2553

  • e-ISSN

  • Svazek periodika

    7

  • Číslo periodika v rámci svazku

    38

  • Stát vydavatele periodika

    US - Spojené státy americké

  • Počet stran výsledku

    16

  • Strana od-do

    62091-62106

  • Kód UT WoS článku

    000387164700097

  • EID výsledku v databázi Scopus