Oncotarget

Research Papers:

Prexasertib, a Chk1/Chk2 inhibitor, increases the effectiveness of conventional therapy in B-/T- cell progenitor acute lymphoblastic leukemia

Andrea Ghelli Luserna Di Rorà, Ilaria Iacobucci _, Enrica Imbrogno, Cristina Papayannidis, Enrico Derenzini, Anna Ferrari, Viviana Guadagnuolo, Valentina Robustelli, Sarah Parisi, Chiara Sartor, Maria Chiara Abbenante, Stefania Paolini and Giovanni Martinelli

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Oncotarget. 2016; 7:53377-53391. https://doi.org/10.18632/oncotarget.10535

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Abstract

Andrea Ghelli Luserna Di Rorà1, Ilaria Iacobucci1,*, Enrica Imbrogno1, Cristina Papayannidis1, Enrico Derenzini1, Anna Ferrari1, Viviana Guadagnuolo1, Valentina Robustelli1, Sarah Parisi1, Chiara Sartor1, Maria Chiara Abbenante1, Stefania Paolini1, Giovanni Martinelli1,*

1Institute of Hematology “L. e A. Seragnoli”, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy

*Co-corresponding authors

Correspondence to:

Ilaria Iacobucci, email: ilaria.iacobucci2@unibo.it

Giovanni Martinelli, email: giovanni.martinelli2@unibo.it

Keywords: CHK1, cell cycle, acute lymphoblastic leukemia, DNA damage response, chemo-sensitizer agent

Received: February 12, 2016    Accepted: June 30, 2016    Published: July 11, 2016

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.


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