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

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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

Rok publikování 2016
Druh Článek v odborném periodiku
Časopis / Zdroj Oncotarget
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Citace
Doi http://dx.doi.org/10.18632/oncotarget.11388
Obor Biochemie
Klíčová slova checkpoint kinase 1/Chk1; SCH900776; nucleoside analogs; chronic lymphocytic leukemia; TP53
Přiložené soubory
Popis 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.
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