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

J 2016

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

ZEMANOVÁ, Jana; Ondřej HYLSE; Jana COLLAKOVA; Pavel VESELY; Alexandra OLTOVÁ et al.

Základní údaje

Originální název

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

Autoři

Vydání

Oncotarget, Albany, Impact Journals, 2016, 1949-2553

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10600 1.6 Biological sciences

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 5.168

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14310/16:00088918

Organizační jednotka

Přírodovědecká fakulta

Klíčová slova anglicky

checkpoint kinase 1/Chk1; SCH900776; nucleoside analogs; chronic lymphocytic leukemia; TP53

Štítky

AKR, EL OK, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 3. 1. 2017 15:55, Ing. Mgr. Věra Pospíšilíková

Anotace

V originále

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.

Návaznosti

LM2015063, projekt VaV

Název: Národní infrastruktura chemické biologie (Akronym: CZ-OPENSCREEN)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CZ-OPENSCREEN: National Infrastructure for Chemical Biology

LQ1601, projekt VaV

Název: CEITEC 2020 (Akronym: CEITEC2020)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CEITEC 2020

MUNI/A/1028/2015, interní kód MU

Název: Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit III (Akronym: VýDiTeHeMa III)

Investor: Masarykova univerzita, Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit III, DO R. 2020_Kategorie A - Specifický výzkum - Studentské výzkumné projekty

NV15-29793A, projekt VaV

Název: Analýza Wnt/PCP jako nástroj pro lepší management chronické lymfocytární leukémie

NV15-33999A, projekt VaV

Název: Vývoj nových nízkomolekulárních protinádorových léčiv na principu syntetické letality

Přiložené soubory

EL_1363771.pdf

Požádat o autorskou verzi souboru

Citovat

ZEMANOVÁ, Jana; Ondřej HYLSE; Jana COLLAKOVA; Pavel VESELY; Alexandra OLTOVÁ; Marek BORSKÝ; Kristína ZÁPRAŽNÁ; Marie KAŠPÁRKOVÁ; Pavlína JANOVSKÁ; Jan VERNER; Jiri KOHOUTEK; Marta DZIMKOVA; Vítězslav BRYJA; Zuzana JAŠKOVÁ; Yvona BRYCHTOVÁ; Kamil PARUCH a Martin TRBUŠEK. Chk1 inhibition significantly potentiates activity of nucleoside analogs in TP53-mutated B-lymphoid cells. Oncotarget. Albany: Impact Journals, 2016, roč. 7, č. 38, s. 62091-62106. ISSN 1949-2553. Dostupné z: https://doi.org/10.18632/oncotarget.11388.

@article{1363771,
   author = {Zemanová, Jana and Hylse, Ondřej and Collakova, Jana and Vesely, Pavel and Oltová, Alexandra and Borský, Marek and Zápražná, Kristína and Kašpárková, Marie and Janovská, Pavlína and Verner, Jan and Kohoutek, Jiri and Dzimkova, Marta and Bryja, Vítězslav and Jašková, Zuzana and Brychtová, Yvona and Paruch, Kamil and Trbušek, Martin},
   article_location = {Albany},
   article_number = {38},
   doi = {https://doi.org/10.18632/oncotarget.11388},
   keywords = {checkpoint kinase 1/Chk1; SCH900776; nucleoside analogs; chronic lymphocytic leukemia; TP53},
   language = {eng},
   issn = {1949-2553},
   journal = {Oncotarget},
   title = {Chk1 inhibition significantly potentiates activity of nucleoside analogs in TP53-mutated B-lymphoid cells},
   volume = {7},
   year = {2016}
}

TY  - JOUR
ID  - 1363771
AU  - Zemanová, Jana - Hylse, Ondřej - Collakova, Jana - Vesely, Pavel - Oltová, Alexandra - Borský, Marek - Zápražná, Kristína - Kašpárková, Marie - Janovská, Pavlína - Verner, Jan - Kohoutek, Jiri - Dzimkova, Marta - Bryja, Vítězslav - Jašková, Zuzana - Brychtová, Yvona - Paruch, Kamil - Trbušek, Martin
PY  - 2016
TI  - Chk1 inhibition significantly potentiates activity of nucleoside analogs in TP53-mutated B-lymphoid cells
JF  - Oncotarget
VL  - 7
IS  - 38
SP  - 62091-62106
EP  - 62091-62106
PB  - Impact Journals
SN  - 19492553
KW  - checkpoint kinase 1/Chk1
KW  - SCH900776
KW  - nucleoside analogs
KW  - chronic lymphocytic leukemia
KW  - TP53
N2  - 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.
ER  -

ZEMANOVÁ, Jana; Ondřej HYLSE; Jana COLLAKOVA; Pavel VESELY; Alexandra OLTOVÁ; Marek BORSKÝ; Kristína ZÁPRAŽNÁ; Marie KAŠPÁRKOVÁ; Pavlína JANOVSKÁ; Jan VERNER; Jiri KOHOUTEK; Marta DZIMKOVA; Vítězslav BRYJA; Zuzana JAŠKOVÁ; Yvona BRYCHTOVÁ; Kamil PARUCH a Martin TRBUŠEK. Chk1 inhibition significantly potentiates activity of nucleoside analogs in TP53-mutated B-lymphoid cells. \textit{Oncotarget}. Albany: Impact Journals, 2016, roč.~7, č.~38, s.~62091-62106. ISSN~1949-2553. Dostupné z: https://doi.org/10.18632/oncotarget.11388.

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