Oncotarget

Research Papers:

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

Jana Zemanova, Ondrej Hylse, Jana Collakova, Pavel Vesely, Alexandra Oltova, Marek Borsky, Kristina Zaprazna, Marie Kasparkova, Pavlina Janovska, Jan Verner, Jiri Kohoutek, Marta Dzimkova, Vitezslav Bryja, Zuzana Jaskova, Yvona Brychtova, Kamil Paruch and Martin Trbusek _

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Oncotarget. 2016; 7:62091-62106. https://doi.org/10.18632/oncotarget.11388

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Abstract

Jana Zemanova1, Ondrej Hylse2,3, Jana Collakova4,5, Pavel Vesely5, Alexandra Oltova1, Marek Borsky1, Kristina Zaprazna6, Marie Kasparkova1, Pavlina Janovska7, Jan Verner1, Jiri Kohoutek8, Marta Dzimkova8, Vitezslav Bryja7,9, Zuzana Jaskova1, Yvona Brychtova1, Kamil Paruch2,3, Martin Trbusek1

1Department of Internal Medicine – Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic

2Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne’s University Hospital, Brno, Czech Republic

3Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Brno, Czech Republic

4Institute of Physical Engineering, Faculty of Mechanical Engineering, Brno University of Technology, Brno, Czech Republic

5CEITEC – Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic

6CEITEC – Central European Institute of Technology, Masaryk University, Brno, Czech Republic

7Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic

8Department of Chemistry and Toxicology, Veterinary Research Institute, Brno, Czech Republic

9Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic

Correspondence to:

Martin Trbusek, email: m.trbusek@volny.cz

Keywords: checkpoint kinase 1/Chk1, SCH900776, nucleoside analogs, chronic lymphocytic leukemia, TP53

Received: February 01, 2016     Accepted: August 08, 2016     Published: August 19, 2016

ABSTRACT

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 γ-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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