Journal
JOURNAL OF HEMATOLOGY & ONCOLOGY
Volume 8, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/s13045-015-0206-5
Keywords
Acute lymphoblastic leukemia; DNA damage; Checkpoint kinase; Drug-sensitivity; New targets
Categories
Funding
- European LeukemiaNet
- AIL
- AIRC research grant [IG 2010 10336, 5x1000 10007]
- Fondazione Del Monte di Bologna e Ravenna
- Ateneo RFO grants
- Project of Integrated Program (PIO)
- Programma di ricerca Regione-Universita
- Fondazione Carisbo, Regione Emilia-Romagna, Bando Ricerca Innovativa
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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 gamma-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.
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