Abstract
Mitotic catastrophe (MC) is induced when stressed cells enter prematurely or inappropriately into mitosis and can be caused by ionizing radiation and anticancer drugs. Foretinib is a multikinase inhibitor whose mechanism of action is incompletely understood. We investigated here the effect of Foretinib on chronic myelogenous leukemia (CML) cell lines either sensitive (IM-S) or resistant (IM-R) to the tyrosine kinase inhibitor Imatinib. Foretinib decreased viability and clonogenic potential of IM-S and IM-R CML cells as well. Foretinib-treated cells exhibited increased size, spindle assembly checkpoint anomalies and enhanced ploidy that collectively evoked mitotic catastrophe (MC). Accordingly, Foretinib-stimulated CML cells displayed decreased expression of Cdk1, Cyclin B1 and Plk1. In addition, Foretinib triggered caspase-2 activation that precedes mitochondrial membrane permeabilization. Accordingly, z-VAD-fmk and a caspase-2 siRNA abolished Foretinib-mediated cell death but failed to affect MC, indicating that Foretinib-mediated apoptosis and MC are two independent events. Anisomycin, a JNK activator, impaired Foretinib-induced MC and inhibition or knockdown of JNK phenotyped its effect on MC. Moreover, we found that Foretinib acted as a potent inhibitor of JNK. Importantly, Foretinib exhibited no or very little effect on normal peripheral blood mononuclear cells, monocytes or melanocytes cells but efficiently inhibited the clonogenic potential of CD34+ cell from CML patients. Collectively, our data show that the multikinase inhibitor Foretinib induces MC in CML cells and other cell lines via JNK-dependent inhibition of Plk1 expression and triggered apoptosis by a caspase 2-mediated mechanism. This unusual mechanism of action may have important implications for the treatment of cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Anilides / pharmacology*
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Anisomycin / pharmacology
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Antigens, CD34 / metabolism
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Antineoplastic Agents / pharmacology
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Benzamides
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CDC2 Protein Kinase / genetics
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CDC2 Protein Kinase / metabolism
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Caspase 2 / genetics
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Caspase 2 / metabolism
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Caspase Inhibitors
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Death*
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Cell Size
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Cell Survival
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Cyclin B1 / genetics
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Cyclin B1 / metabolism
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Cysteine Endopeptidases / genetics
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Cysteine Endopeptidases / metabolism
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Enzyme Activation
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Enzyme Assays
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Humans
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Imatinib Mesylate
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K562 Cells / drug effects
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / metabolism
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M Phase Cell Cycle Checkpoints
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MAP Kinase Signaling System*
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Melanocytes / drug effects
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Melanocytes / metabolism
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Mitosis / drug effects
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Phenotype
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Piperazines / pharmacology
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Ploidies
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Polo-Like Kinase 1
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Pyrimidines / pharmacology
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Quinolines / pharmacology*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Transfection
Substances
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Amino Acid Chloromethyl Ketones
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Anilides
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Antigens, CD34
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Antineoplastic Agents
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Benzamides
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CCNB1 protein, human
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Caspase Inhibitors
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Cell Cycle Proteins
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Cyclin B1
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GSK 1363089
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Piperazines
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pyrimidines
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Quinolines
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RNA, Small Interfering
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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Anisomycin
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Imatinib Mesylate
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Protein Serine-Threonine Kinases
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CDC2 Protein Kinase
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CASP2 protein, human
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Caspase 2
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Cysteine Endopeptidases