title: Prexasertib, a Chk1/Chk2 inhibitor, increases the effectiveness of conventional therapy in B-/T- cell progenitor acute lymphoblastic leukemia.
abstract: During the last few years many Checkpoint kinase 1/2 (Chk1/Chk2) inhibitors have been developed for the treatment of different type of cancers. In this study we evaluated the efficacy of the Chk 1/2 inhibitor prexasertib mesylate monohydrate in B-/T- cell progenitor acute lymphoblastic leukemia (ALL) as single agent and in combination with other drugs. The prexasertib reduced the cell viability in a dose and time dependent manner in all the treated cell lines. The cytotoxic activity was confirmed by the increment of apoptotic cells (Annexin V/Propidium Iodide staining), by the increase of γH2A.X protein expression and by the activation of different apoptotic markers (Parp-1 and pro-Caspase3 cleavage). Furthermore, the inhibition of Chk1 changed the cell cycle profile. In order to evaluate the chemo-sensitizer activity of the compound, different cell lines were treated for 24 and 48 hours with prexasertib in combination with other drugs (imatinib, dasatinib and clofarabine). The results from cell line models were strengthened in primary leukemic blasts isolated from peripheral blood of adult acute lymphoblastic leukemia patients. In this study we highlighted the mechanism of action and the effectiveness of prexasertib as single agent or in combination with other conventional drugs like imatinib, dasatinib and clofarabine in the treatment of B-/T-ALL.
authors.affiliation: Institute of Hematology "L. e A. Seragnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ghelli Luserna Di Rorà
authors.affiliation: Institute of Hematology "L. e A. Seragnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Iacobucci
authors.affiliation: Institute of Hematology "L. e A. Seragnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Imbrogno
authors.affiliation: Institute of Hematology "L. e A. Seragnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Papayannidis
authors.affiliation: Institute of Hematology "L. e A. Seragnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Derenzini
authors.affiliation: Institute of Hematology "L. e A. Seragnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ferrari
authors.affiliation: Institute of Hematology "L. e A. Seragnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Guadagnuolo
authors.affiliation: Institute of Hematology "L. e A. Seragnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Robustelli
authors.affiliation: Institute of Hematology "L. e A. Seragnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Parisi
authors.affiliation: Institute of Hematology "L. e A. Seragnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Sartor
authors.affiliation: Institute of Hematology "L. e A. Seragnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Abbenante
authors.affiliation: Institute of Hematology "L. e A. Seragnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Paolini
authors.affiliation: Institute of Hematology "L. e A. Seragnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
mesh_terms: D000227:Adenine Nucleotides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001087:Arabinonucleosides / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077866:Clofarabine; D000069439:Dasatinib / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*
chemical_list: D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011720:Pyrazoles; C000608121:prexasertib; D000077866:Clofarabine; D000068877:Imatinib Mesylate; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D000069439:Dasatinib
keywords: CHK1; DNA damage response; acute lymphoblastic leukemia; cell cycle; chemo-sensitizer agent