In vitro and in vivo single-agent efficacy of checkpoint kinase inhibition in acute lymphoblastic leukemia
Copyright policy )In vitro and in vivo single-agent efficacy of checkpoint kinase inhibition in acute lymphoblastic leukemia
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).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.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.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.
Cancer Research, 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, Cell Survival, Blotting, Western, 610, Apoptosis, Acute lymphoblastic leukemia, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Settore MED/05 - PATOLOGIA CLINICA, Cell Line, Tumor, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Animals, Humans, New targets, Molecular Biology, Protein Kinase Inhibitors, Benzodiazepinones, Leukemia, Experimental, Dose-Response Relationship, Drug, Gene Expression Regulation, Leukemic, Research, Gene Expression Profiling, Drug-sensitivity, Cell Cycle, Hematology, Acute lymphoblastic leukemia; Checkpoint kinase; DNA damage; Drug-sensitivity; New targets; Animals; Apoptosis; Benzodiazepinones; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Survival; Checkpoint Kinase 1; 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, Mice, Inbred C57BL, Oncology, Microscopy, Fluorescence, Checkpoint Kinase 1, Neoplastic Stem Cells, DNA damage, Checkpoint kinase, Protein Kinases
Cancer Research, 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, Cell Survival, Blotting, Western, 610, Apoptosis, Acute lymphoblastic leukemia, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Settore MED/05 - PATOLOGIA CLINICA, Cell Line, Tumor, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Animals, Humans, New targets, Molecular Biology, Protein Kinase Inhibitors, Benzodiazepinones, Leukemia, Experimental, Dose-Response Relationship, Drug, Gene Expression Regulation, Leukemic, Research, Gene Expression Profiling, Drug-sensitivity, Cell Cycle, Hematology, Acute lymphoblastic leukemia; Checkpoint kinase; DNA damage; Drug-sensitivity; New targets; Animals; Apoptosis; Benzodiazepinones; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Survival; Checkpoint Kinase 1; 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, Mice, Inbred C57BL, Oncology, Microscopy, Fluorescence, Checkpoint Kinase 1, Neoplastic Stem Cells, DNA damage, Checkpoint kinase, Protein Kinases
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