title: Chk1 inhibition significantly potentiates activity of nucleoside analogs in TP53-mutated B-lymphoid cells.
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.
authors.affiliation: Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Zemanova
authors.affiliation: Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.|Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Hylse
authors.affiliation: Institute of Physical Engineering, Faculty of Mechanical Engineering, Brno University of Technology, Brno, Czech Republic.|CEITEC - Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Collakova
authors.affiliation: CEITEC - Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Vesely
authors.affiliation: Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Oltova
authors.affiliation: Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Borsky
authors.affiliation: CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Kristina
authors.initials: K
authors.lastname: Zaprazna
authors.affiliation: Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Kasparkova
authors.affiliation: Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Pavlina
authors.initials: P
authors.lastname: Janovska
authors.affiliation: Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Verner
authors.affiliation: Department of Chemistry and Toxicology, Veterinary Research Institute, Brno, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Kohoutek
authors.affiliation: Department of Chemistry and Toxicology, Veterinary Research Institute, Brno, Czech Republic.
authors.forename: Marta
authors.initials: M
authors.lastname: Dzimkova
authors.affiliation: Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.|Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic.
authors.forename: Vitezslav
authors.initials: V
authors.lastname: Bryja
authors.affiliation: Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Jaskova
authors.affiliation: Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Yvona
authors.initials: Y
authors.lastname: Brychtova
authors.affiliation: Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.|Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Kamil
authors.initials: K
authors.lastname: Paruch
authors.affiliation: Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Trbusek
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors*; D003561:Cytarabine / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis; D009154:Mutation; D009705:Nucleosides / Q000235:genetics*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000093542:Gemcitabine
chemical_list: C559815:MK-8776; D009705:Nucleosides; D011720:Pyrazoles; D011743:Pyrimidines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003561:Cytarabine; D003841:Deoxycytidine; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D014740:Vidarabine; C024352:fludarabine; D000093542:Gemcitabine
keywords: SCH900776; TP53; checkpoint kinase 1/Chk1; chronic lymphocytic leukemia; nucleoside analogs