Background: Although progress in children, in adults, ALL still carries a dismal outcome. Here, we explored the in vitro and in vivo activity of PF-00477736 (Pfizer), a potent, selective ATP-competitive small-molecule inhibitor of checkpoint kinase 1 (Chk1) and with lower efficacy of checkpoint kinase 2 (Chk2). Methods: The effectiveness of PF-00477736 as single agent in B-/T-ALL was evaluated in vitro and in vivo studies as a single agent. The efficacy of the compound in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed using different B-/T-ALL cell lines. Finally, the action of PF-00477736 was assessed in vivo using leukemic mouse generated by a single administration of the tumorigenic agent n-ethyl-n-nitrosourea. Results: Chk1 and Chk2 are overexpressed concomitant with the presence of genetic damage as suggested by the nuclear labeling for γ-H2A.X (Ser139) in 68 % of ALL patients. In human B-and T-ALL cell lines, inhibition of Chk1/2 as a single treatment strategy efficiently triggered the Chk1-Cdc25-Cdc2 pathway resulting in a dose-and time-dependent cytotoxicity, induction of apoptosis, and increased DNA damage. Moreover, treatment with PF-00477736 showed efficacy ex vivo in primary leukemic blasts separated from 14 adult ALL patients and in vivo in mice transplanted with T-ALL, arguing in favor of its future clinical evaluation in leukemia. Conclusions: In vitro, ex vivo, and in vivo results support the inhibition of Chk1 as a new therapeutic strategy in acute lymphoblastic leukemia, and they provide a strong rationale for its future clinical investigation.
In vitro and in vivo single-agent efficacy of checkpoint kinase inhibition in acute lymphoblastic leukemia / I. Iacobucci, A.G.L. Di Rorà, M.V.V. Falzacappa, C. Agostinelli, E. Derenzini, A. Ferrari, C. Papayannidis, A. Lonetti, S. Righi, E. Imbrogno, S. Pomella, C. Venturi, V. Guadagnuolo, F. Cattina, E. Ottaviani, M.C. Abbenante, A. Vitale, L. Elia, D. Russo, P.L. Zinzani, S. Pileri, P.G. Pelicci, G. Martinelli. - In: JOURNAL OF HEMATOLOGY & ONCOLOGY. - ISSN 1756-8722. - 8:1(2015 Nov 05).
|Titolo:||In vitro and in vivo single-agent efficacy of checkpoint kinase inhibition in acute lymphoblastic leukemia|
PELICCI, PIER GIUSEPPE (Penultimo)
|Parole Chiave:||acute lymphoblastic leukemia; checkpoint kinase; dna damage; drug-sensitivity; new targets; animals; apoptosis; benzodiazepinones; blotting, western; cell cycle; cell line, tumor; cell survival; dose-response relationship, drug; gene expression profiling; gene expression regulation, leukemic; humans; leukemia, experimental; mice, inbred c57bl; microscopy, fluorescence; neoplastic stem cells; precursor b-cell lymphoblastic leukemia-lymphoma; precursor t-cell lymphoblastic leukemia-lymphoma; protein kinase inhibitors; protein kinases; pyrazoles; survival analysis; hematology; oncology; cancer research; molecular biology|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||5-nov-2015|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1186/s13045-015-0206-5|
|Appare nelle tipologie:||01 - Articolo su periodico|