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

Autor: Yvona Brychtová, Alexandra Oltová, Pavel Vesely, Jan Verner, Martin Trbušek, Kristina Zaprazna, Pavlína Janovská, Jiri Kohoutek, Zuzana Jašková, Marek Borsky, Ondrej Hylse, Vitezslav Bryja, Kamil Paruch, Marta Dzimkova, Marie Kasparkova, Jana Zemanová, Jana Collakova
Rok vydání: 2016
Předmět:
0301 basic medicine
Czech
Chronic lymphocytic leukemia
Apoptosis
Deoxycytidine
Mice
0302 clinical medicine
TP53
nucleoside analogs
B-Lymphocytes
Hematology
Cell Cycle
Cytarabine
Nucleosides
3. Good health
Fludarabine
Leukemia
Oncology
030220 oncology & carcinogenesis
language
Vidarabine
Research Paper
Signal Transduction
medicine.drug
medicine.medical_specialty
Cell Survival
Mitosis
chronická lymfocytární leukemie
Mice
Transgenic
checkpoint kinase 1/Chk1
03 medical and health sciences
Cell Line
Tumor
Internal medicine
kontrolní bod kinázy 1/Chk1
medicine
Animals
Humans
CHEK1
SCH900776
Cell Proliferation
Nucleoside analogue
business.industry
medicine.disease
Leukemia
Lymphocytic
Chronic
B-Cell
Gemcitabine
language.human_language
Pyrimidines
030104 developmental biology
Checkpoint Kinase 1
Mutation
Immunology
Cancer research
chronic lymphocytic leukemia
Pyrazoles
analogy purinových nukleosidů
Drug Screening Assays
Antitumor
Tumor Suppressor Protein p53
business
Zdroj: Oncotarget
Oncotarget. 2016, vol. 7, issue 38, p. 1-16.
ISSN: 1949-2553
Popis: // Jana Zemanova 1 , Ondrej Hylse 2, 3 , Jana Collakova 4, 5 , Pavel Vesely 5 , Alexandra Oltova 1 , Marek Borsky 1 , Kristina Zaprazna 6 , Marie Kasparkova 1 , Pavlina Janovska 7 , Jan Verner 1 , Jiri Kohoutek 8 , Marta Dzimkova 8 , Vitezslav Bryja 7, 9 , Zuzana Jaskova 1 , Yvona Brychtova 1 , Kamil Paruch 2, 3 , Martin Trbusek 1 1 Department of Internal Medicine – Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic 2 Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne’s University Hospital, Brno, Czech Republic 3 Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Brno, Czech Republic 4 Institute of Physical Engineering, Faculty of Mechanical Engineering, Brno University of Technology, Brno, Czech Republic 5 CEITEC – Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic 6 CEITEC – Central European Institute of Technology, Masaryk University, Brno, Czech Republic 7 Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic 8 Department of Chemistry and Toxicology, Veterinary Research Institute, Brno, Czech Republic 9 Department 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.
Databáze: OpenAIRE
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