title: Mechanism of action of the multikinase inhibitor Foretinib.
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.
authors.affiliation: INSERM U895, Centre Meditérranéen de Médecine Moléculaire, Nice, France.
authors.forename: Maeva
authors.initials: M
authors.lastname: Dufies
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jacquel
authors.forename: Guillaume
authors.initials: G
authors.lastname: Robert
authors.forename: Thomas
authors.initials: T
authors.lastname: Cluzeau
authors.forename: Alexandre
authors.initials: A
authors.lastname: Puissant
authors.forename: Nina
authors.initials: N
authors.lastname: Fenouille
authors.forename: Laurence
authors.initials: L
authors.lastname: Legros
authors.forename: Sophie
authors.initials: S
authors.lastname: Raynaud
authors.forename: Jill-Patrice
authors.initials: JP
authors.lastname: Cassuto
authors.forename: Fréderic
authors.initials: F
authors.lastname: Luciano
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology*; D000841:Anisomycin / Q000494:pharmacology; D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D048429:Cell Size; D002470:Cell Survival; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D057075:Enzyme Assays; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells / Q000187:drug effects; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints; D020935:MAP Kinase Signaling System; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology; D011003:Ploidies; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000097869:Polo-Like Kinase 1
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000813:Anilides; D000841:Anisomycin; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001549:Benzamides; D016203:CDC2 Protein Kinase; D053143:Caspase 2; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D003546:Cysteine Endopeptidases; D000068877:Imatinib Mesylate; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D011804:Quinolines; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1; C534699:CCNB1 protein, human; C544831:GSK 1363089; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C490360:CASP2 protein, human