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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 |
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| creator | Dufies, Maeva Jacquel, Arnaud Robert, Guillaume Cluzeau, Thomas Puissant, Alexandre Fenouille, Nina Legros, Laurence Raynaud, Sophie Cassuto, Jill-Patrice Luciano, Fréderic Auberger, Patrick |
| description | 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. |
| doi_str_mv | 10.4161/cc.10.23.18323 |
| format | article |
| fullrecord | <record><control><sourceid>hal_cross</sourceid><recordid>TN_cdi_hal_primary_oai_HAL_hal_00771381v1</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>oai_HAL_hal_00771381v1</sourcerecordid><originalsourceid>FETCH-LOGICAL-c501t-3a4727ea43c3cd0d8547857c17385d2cc7ca31bea8262cd95b4e49a502b827393</originalsourceid><addsrcrecordid>eNqFkE1P3DAQhq0KVD7aa48oVw7ZeuwYO72hBUqlrbi0Z8uZONopib2ys0X8exLS7g1x8qvR84w8L2NfgK8quIKviKspCrkCI4X8wE5BKSgrztXRnKUpK-Bwws5y_sO5MLqGj-xEiGkoND9l33563LpAeShiVzgcKYY5jVtfDPt-pEcKLvuCwpYaGmMq7mLyIwVqPrHjzvXZf_73nrPfd7e_1vfl5uH7j_X1pkTFYSylq7TQ3lUSJba8NarSRmkELY1qBaJGJ6HxzogrgW2tmspXtVNcNEZoWctzdrns3bre7hINLj3b6MjeX2_sPONca5AG_sLErhYWU8w5-e4gALdzYRZxjkLa18Im4WIRdvtm8O0B_9_QBPAF6F1ofW4oZiQf0B_QaaNLI2HvDzvhHeVm35HP6_Xyk13bTU69OBS6mAb3FFPf2tE99zF1yQWkbOUbN7wALqCbMQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Mechanism of action of the multikinase inhibitor Foretinib</title><source>Taylor and Francis Science and Technology Collection</source><source>PubMed Central</source><creator>Dufies, Maeva ; Jacquel, Arnaud ; Robert, Guillaume ; Cluzeau, Thomas ; Puissant, Alexandre ; Fenouille, Nina ; Legros, Laurence ; Raynaud, Sophie ; Cassuto, Jill-Patrice ; Luciano, Fréderic ; Auberger, Patrick</creator><creatorcontrib>Dufies, Maeva ; Jacquel, Arnaud ; Robert, Guillaume ; Cluzeau, Thomas ; Puissant, Alexandre ; Fenouille, Nina ; Legros, Laurence ; Raynaud, Sophie ; Cassuto, Jill-Patrice ; Luciano, Fréderic ; Auberger, Patrick</creatorcontrib><description>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.</description><identifier>ISSN: 1538-4101</identifier><identifier>EISSN: 1551-4005</identifier><identifier>DOI: 10.4161/cc.10.23.18323</identifier><identifier>PMID: 22101270</identifier><language>eng</language><publisher>United States: Taylor & Francis</publisher><subject>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</subject><ispartof>Cell cycle (Georgetown, Tex.), 2011-12, Vol.10 (23), p.4138-4148</ispartof><rights>Copyright © 2011 Landes Bioscience 2011</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c501t-3a4727ea43c3cd0d8547857c17385d2cc7ca31bea8262cd95b4e49a502b827393</citedby><orcidid>0000-0002-2481-8275 ; 0000-0001-5062-8048 ; 0000-0003-1732-0388 ; 0000-0002-3997-9282</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22101270$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-00771381$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Dufies, Maeva</creatorcontrib><creatorcontrib>Jacquel, Arnaud</creatorcontrib><creatorcontrib>Robert, Guillaume</creatorcontrib><creatorcontrib>Cluzeau, Thomas</creatorcontrib><creatorcontrib>Puissant, Alexandre</creatorcontrib><creatorcontrib>Fenouille, Nina</creatorcontrib><creatorcontrib>Legros, Laurence</creatorcontrib><creatorcontrib>Raynaud, Sophie</creatorcontrib><creatorcontrib>Cassuto, Jill-Patrice</creatorcontrib><creatorcontrib>Luciano, Fréderic</creatorcontrib><creatorcontrib>Auberger, Patrick</creatorcontrib><title>Mechanism of action of the multikinase inhibitor Foretinib</title><title>Cell cycle (Georgetown, Tex.)</title><addtitle>Cell Cycle</addtitle><description>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.</description><subject>Amino Acid Chloromethyl Ketones</subject><subject>Amino Acid Chloromethyl Ketones - pharmacology</subject><subject>Anilides</subject><subject>Anilides - pharmacology</subject><subject>Anisomycin</subject><subject>Anisomycin - pharmacology</subject><subject>Antigens, CD34</subject><subject>Antigens, CD34 - metabolism</subject><subject>Antineoplastic Agents</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Benzamides</subject><subject>Binding</subject><subject>Biology</subject><subject>Bioscience</subject><subject>Calcium</subject><subject>Cancer</subject><subject>Caspase 2</subject><subject>Caspase 2 - genetics</subject><subject>Caspase 2 - metabolism</subject><subject>Caspase Inhibitors</subject><subject>CDC2 Protein Kinase</subject><subject>CDC2 Protein Kinase - genetics</subject><subject>CDC2 Protein Kinase - metabolism</subject><subject>Cell</subject><subject>Cell Cycle Proteins</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cell Death</subject><subject>Cell Size</subject><subject>Cell Survival</subject><subject>Cycle</subject><subject>Cyclin B1</subject><subject>Cyclin B1 - genetics</subject><subject>Cyclin B1 - metabolism</subject><subject>Cysteine Endopeptidases</subject><subject>Cysteine Endopeptidases - genetics</subject><subject>Cysteine Endopeptidases - metabolism</subject><subject>Development Biology</subject><subject>Enzyme Activation</subject><subject>Enzyme Assays</subject><subject>Humans</subject><subject>Imatinib Mesylate</subject><subject>K562 Cells</subject><subject>K562 Cells - drug effects</subject><subject>Landes</subject><subject>Leukemia, Myelogenous, Chronic, BCR-ABL Positive</subject><subject>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy</subject><subject>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology</subject><subject>Leukocytes, Mononuclear</subject><subject>Leukocytes, Mononuclear - drug effects</subject><subject>Leukocytes, Mononuclear - metabolism</subject><subject>Life Sciences</subject><subject>M Phase Cell Cycle Checkpoints</subject><subject>MAP Kinase Signaling System</subject><subject>Melanocytes</subject><subject>Melanocytes - drug effects</subject><subject>Melanocytes - metabolism</subject><subject>Mitosis</subject><subject>Mitosis - drug effects</subject><subject>Organogenesis</subject><subject>Phenotype</subject><subject>Piperazines</subject><subject>Piperazines - pharmacology</subject><subject>Ploidies</subject><subject>Polo-Like Kinase 1</subject><subject>Protein Kinase Inhibitors</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Serine-Threonine Kinases - genetics</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Protein-Serine-Threonine Kinases</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Pyrimidines</subject><subject>Pyrimidines - pharmacology</subject><subject>Quinolines</subject><subject>Quinolines - pharmacology</subject><subject>RNA, Small Interfering</subject><subject>RNA, Small Interfering - genetics</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Transfection</subject><issn>1538-4101</issn><issn>1551-4005</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><recordid>eNqFkE1P3DAQhq0KVD7aa48oVw7ZeuwYO72hBUqlrbi0Z8uZONopib2ys0X8exLS7g1x8qvR84w8L2NfgK8quIKviKspCrkCI4X8wE5BKSgrztXRnKUpK-Bwws5y_sO5MLqGj-xEiGkoND9l33563LpAeShiVzgcKYY5jVtfDPt-pEcKLvuCwpYaGmMq7mLyIwVqPrHjzvXZf_73nrPfd7e_1vfl5uH7j_X1pkTFYSylq7TQ3lUSJba8NarSRmkELY1qBaJGJ6HxzogrgW2tmspXtVNcNEZoWctzdrns3bre7hINLj3b6MjeX2_sPONca5AG_sLErhYWU8w5-e4gALdzYRZxjkLa18Im4WIRdvtm8O0B_9_QBPAF6F1ofW4oZiQf0B_QaaNLI2HvDzvhHeVm35HP6_Xyk13bTU69OBS6mAb3FFPf2tE99zF1yQWkbOUbN7wALqCbMQ</recordid><startdate>20111201</startdate><enddate>20111201</enddate><creator>Dufies, Maeva</creator><creator>Jacquel, Arnaud</creator><creator>Robert, Guillaume</creator><creator>Cluzeau, Thomas</creator><creator>Puissant, Alexandre</creator><creator>Fenouille, Nina</creator><creator>Legros, Laurence</creator><creator>Raynaud, Sophie</creator><creator>Cassuto, Jill-Patrice</creator><creator>Luciano, Fréderic</creator><creator>Auberger, Patrick</creator><general>Taylor & Francis</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-2481-8275</orcidid><orcidid>https://orcid.org/0000-0001-5062-8048</orcidid><orcidid>https://orcid.org/0000-0003-1732-0388</orcidid><orcidid>https://orcid.org/0000-0002-3997-9282</orcidid></search><sort><creationdate>20111201</creationdate><title>Mechanism of action of the multikinase inhibitor Foretinib</title><author>Dufies, Maeva ; Jacquel, Arnaud ; Robert, Guillaume ; Cluzeau, Thomas ; Puissant, Alexandre ; Fenouille, Nina ; Legros, Laurence ; Raynaud, Sophie ; Cassuto, Jill-Patrice ; Luciano, Fréderic ; Auberger, Patrick</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c501t-3a4727ea43c3cd0d8547857c17385d2cc7ca31bea8262cd95b4e49a502b827393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Amino Acid Chloromethyl Ketones</topic><topic>Amino Acid Chloromethyl Ketones - pharmacology</topic><topic>Anilides</topic><topic>Anilides - pharmacology</topic><topic>Anisomycin</topic><topic>Anisomycin - pharmacology</topic><topic>Antigens, CD34</topic><topic>Antigens, CD34 - metabolism</topic><topic>Antineoplastic Agents</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Benzamides</topic><topic>Binding</topic><topic>Biology</topic><topic>Bioscience</topic><topic>Calcium</topic><topic>Cancer</topic><topic>Caspase 2</topic><topic>Caspase 2 - genetics</topic><topic>Caspase 2 - metabolism</topic><topic>Caspase Inhibitors</topic><topic>CDC2 Protein Kinase</topic><topic>CDC2 Protein Kinase - genetics</topic><topic>CDC2 Protein Kinase - metabolism</topic><topic>Cell</topic><topic>Cell Cycle Proteins</topic><topic>Cell Cycle Proteins - genetics</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Cell Death</topic><topic>Cell Size</topic><topic>Cell Survival</topic><topic>Cycle</topic><topic>Cyclin B1</topic><topic>Cyclin B1 - genetics</topic><topic>Cyclin B1 - 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drug effects</topic><topic>Organogenesis</topic><topic>Phenotype</topic><topic>Piperazines</topic><topic>Piperazines - pharmacology</topic><topic>Ploidies</topic><topic>Polo-Like Kinase 1</topic><topic>Protein Kinase Inhibitors</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Serine-Threonine Kinases - genetics</topic><topic>Protein Serine-Threonine Kinases - metabolism</topic><topic>Protein-Serine-Threonine Kinases</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins</topic><topic>Proto-Oncogene Proteins - genetics</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Pyrimidines</topic><topic>Pyrimidines - pharmacology</topic><topic>Quinolines</topic><topic>Quinolines - pharmacology</topic><topic>RNA, Small Interfering</topic><topic>RNA, Small Interfering - genetics</topic><topic>RNA, Small Interfering - metabolism</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dufies, Maeva</creatorcontrib><creatorcontrib>Jacquel, Arnaud</creatorcontrib><creatorcontrib>Robert, Guillaume</creatorcontrib><creatorcontrib>Cluzeau, Thomas</creatorcontrib><creatorcontrib>Puissant, Alexandre</creatorcontrib><creatorcontrib>Fenouille, Nina</creatorcontrib><creatorcontrib>Legros, Laurence</creatorcontrib><creatorcontrib>Raynaud, Sophie</creatorcontrib><creatorcontrib>Cassuto, Jill-Patrice</creatorcontrib><creatorcontrib>Luciano, Fréderic</creatorcontrib><creatorcontrib>Auberger, Patrick</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Cell cycle (Georgetown, Tex.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dufies, Maeva</au><au>Jacquel, Arnaud</au><au>Robert, Guillaume</au><au>Cluzeau, Thomas</au><au>Puissant, Alexandre</au><au>Fenouille, Nina</au><au>Legros, Laurence</au><au>Raynaud, Sophie</au><au>Cassuto, Jill-Patrice</au><au>Luciano, Fréderic</au><au>Auberger, Patrick</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanism of action of the multikinase inhibitor Foretinib</atitle><jtitle>Cell cycle (Georgetown, Tex.)</jtitle><addtitle>Cell Cycle</addtitle><date>2011-12-01</date><risdate>2011</risdate><volume>10</volume><issue>23</issue><spage>4138</spage><epage>4148</epage><pages>4138-4148</pages><issn>1538-4101</issn><eissn>1551-4005</eissn><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.</abstract><cop>United States</cop><pub>Taylor & Francis</pub><pmid>22101270</pmid><doi>10.4161/cc.10.23.18323</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-2481-8275</orcidid><orcidid>https://orcid.org/0000-0001-5062-8048</orcidid><orcidid>https://orcid.org/0000-0003-1732-0388</orcidid><orcidid>https://orcid.org/0000-0002-3997-9282</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Cell cycle (Georgetown, Tex.), 2011-12, Vol.10 (23), p.4138-4148 |
| issn | 1538-4101 1551-4005 |
| language | eng |
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| source | Taylor and Francis Science and Technology Collection; PubMed Central |
| 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 |
| title | Mechanism of action of the multikinase inhibitor Foretinib |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-22T15%3A23%3A06IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-hal_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Mechanism%20of%20action%20of%20the%20multikinase%20inhibitor%20Foretinib&rft.jtitle=Cell%20cycle%20(Georgetown,%20Tex.)&rft.au=Dufies,%20Maeva&rft.date=2011-12-01&rft.volume=10&rft.issue=23&rft.spage=4138&rft.epage=4148&rft.pages=4138-4148&rft.issn=1538-4101&rft.eissn=1551-4005&rft_id=info:doi/10.4161/cc.10.23.18323&rft_dat=%3Chal_cross%3Eoai_HAL_hal_00771381v1%3C/hal_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c501t-3a4727ea43c3cd0d8547857c17385d2cc7ca31bea8262cd95b4e49a502b827393%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_id=info:pmid/22101270&rfr_iscdi=true |