Mechanism of action of the multikinase inhibitor Foretinib

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 Foreti...

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Published in:Cell cycle (Georgetown, Tex.) Tex.), 2011-12, Vol.10 (23), p.4138-4148
Main Authors: Dufies, Maeva, Jacquel, Arnaud, Robert, Guillaume, Cluzeau, Thomas, Puissant, Alexandre, Fenouille, Nina, Legros, Laurence, Raynaud, Sophie, Cassuto, Jill-Patrice, Luciano, Fréderic, Auberger, Patrick
Format: Article
Language:English
Subjects:
Amino Acid Chloromethyl Ketones
Amino Acid Chloromethyl Ketones - pharmacology
Anilides
Anilides - pharmacology
Anisomycin
Anisomycin - pharmacology
Antigens, CD34
Antigens, CD34 - metabolism
Antineoplastic Agents
Antineoplastic Agents - pharmacology
Benzamides
Binding
Biology
Bioscience
Calcium
Cancer
Caspase 2
Caspase 2 - genetics
Caspase 2 - metabolism
Caspase Inhibitors
CDC2 Protein Kinase
CDC2 Protein Kinase - genetics
CDC2 Protein Kinase - metabolism
Cell
Cell Cycle Proteins
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Death
Cell Size
Cell Survival
Cycle
Cyclin B1
Cyclin B1 - genetics
Cyclin B1 - metabolism
Cysteine Endopeptidases
Cysteine Endopeptidases - genetics
Cysteine Endopeptidases - metabolism
Development Biology
Enzyme Activation
Enzyme Assays
Humans
Imatinib Mesylate
K562 Cells
K562 Cells - drug effects
Landes
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology
Leukocytes, Mononuclear
Leukocytes, Mononuclear - drug effects
Leukocytes, Mononuclear - metabolism
Life Sciences
M Phase Cell Cycle Checkpoints
MAP Kinase Signaling System
Melanocytes
Melanocytes - drug effects
Melanocytes - metabolism
Mitosis
Mitosis - drug effects
Organogenesis
Phenotype
Piperazines
Piperazines - pharmacology
Ploidies
Polo-Like Kinase 1
Protein Kinase Inhibitors
Protein Kinase Inhibitors - pharmacology
Protein Serine-Threonine Kinases - genetics
Protein Serine-Threonine Kinases - metabolism
Protein-Serine-Threonine Kinases
Proteins
Proto-Oncogene Proteins
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Pyrimidines
Pyrimidines - pharmacology
Quinolines
Quinolines - pharmacology
RNA, Small Interfering
RNA, Small Interfering - genetics
RNA, Small Interfering - metabolism
Transfection
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Summary: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.
ISSN:1538-4101
1551-4005
DOI:10.4161/cc.10.23.18323