The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival
IL-6 and downstream JAK-dependent signaling pathways have critical roles in the pathophysiology of multiple myeloma (MM). We investigated the effects of a novel small-molecule JAK inhibitor (AZD1480) on IL-6/JAK signal transduction and its biological consequences on the human myeloma-derived cell li...
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| Veröffentlicht in: | Leukemia 2011-03, Vol.25 (3), p.538-550 |
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| creator | Scuto, A Krejci, P Popplewell, L Wu, J Wang, Y Kujawski, M Kowolik, C Xin, H Chen, L Kretzner, L Yu, H Wilcox, W R Yen, Y Forman, S Jove, R |
| description | IL-6 and downstream JAK-dependent signaling pathways have critical roles in the pathophysiology of multiple myeloma (MM). We investigated the effects of a novel small-molecule JAK inhibitor (AZD1480) on IL-6/JAK signal transduction and its biological consequences on the human myeloma-derived cell lines U266 and Kms.11. At low micromolar concentrations, AZD1480 blocks cell proliferation and induces apoptosis of myeloma cell lines. These biological responses to AZD1480 are associated with concomitant inhibition of phosphorylation of JAK2, STAT3 and MAPK signaling proteins. In addition, there is inhibition of expression of STAT3 target genes, particularly Cyclin D2. Examination of a wider variety of myeloma cells (RPMI 8226, OPM-2, NCI-H929, Kms.18, MM1.S and IM-9), as well as primary myeloma cells, showed that AZD1480 has broad efficacy. In contrast, viability of normal peripheral blood (PB) mononuclear cells and CD138
+
cells derived from healthy controls was not significantly inhibited. Importantly, AZD1480 induces cell death of Kms.11 cells grown in the presence of HS-5 bone marrow (BM)-derived stromal cells and inhibits tumor growth in a Kms.11 xenograft mouse model, accompanied with inhibition of phospho-FGFR3, phospho-JAK2, phospho-STAT3 and Cyclin D2 levels. In sum, AZD1480 blocks proliferation, survival, FGFR3 and JAK/STAT3 signaling in myeloma cells cultured alone or cocultured with BM stromal cells, and
in vivo
. Thus, AZD1480 represents a potential new therapeutic agent for patients with MM. |
| doi_str_mv | 10.1038/leu.2010.289 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3216671</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A251855812</galeid><sourcerecordid>A251855812</sourcerecordid><originalsourceid>FETCH-LOGICAL-c702t-86523c768bda0e1ae6407af35874131b11ca7f3b19901942d86f8e0e42d84bff3</originalsourceid><addsrcrecordid>eNqFks9v0zAUxyMEYl3hxhlZIOCyFP-IY-eCVA06fkxCgnLhYjmpk3g4drGTTrvzh-OsZV3REMohjt_nfV_ee98keYLgDEHCXxs1zDCMX5gX95IJylieUkrR_WQCOWdpXuDsKDkO4QLCMZg_TI4wQnlGEZskv5atAtZtlAEf55-Atq0ude88mH9_izIOQWlc9SOAr8v5kgBpV2BxtvhCQNCNlUbb5gR4FQbTx2PMBmFYr-NF0M4CV4N26KQF3ZUyrpOgUsaAxrvLvr2WCoPf6I00j5IHtTRBPd69p8m3xbvl6fv0_PPZh9P5eVoxiPuU5xSTiuW8XEmokFR5BpmsCeUsQwSVCFWS1aRERQFRkeEVz2uuoBpPWVnXZJq82equh7JTq0rZ3ksj1l530l8JJ7U4jFjdisZtBMEozxmKAq92At79HFToRafD2JW0yg1B8JwxwjjP_k_S-POcUxbJZ3-RF27wcbgjRIuCZLHrafL8XxCOm2QEx7p7qpFGCW1rF7uoxsJijimKchyNWrM7qPisVKcrZ1Wt4_1BwstbCa2Spm-DM0MflxwOwZMtWHkXglf1zWgRFKNZRTSrGM0qolkj_vT2Om7gP-6MwIsdIEMlTe2lrXTYcyQumV4PO91yIYZso_x-OncW_g3Mefz_</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2645732737</pqid></control><display><type>article</type><title>The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival</title><source>MEDLINE</source><source>Springer Nature - Complete Springer Journals</source><source>Nature Journals Online</source><source>EZB Electronic Journals Library</source><creator>Scuto, A ; Krejci, P ; Popplewell, L ; Wu, J ; Wang, Y ; Kujawski, M ; Kowolik, C ; Xin, H ; Chen, L ; Kretzner, L ; Yu, H ; Wilcox, W R ; Yen, Y ; Forman, S ; Jove, R</creator><creatorcontrib>Scuto, A ; Krejci, P ; Popplewell, L ; Wu, J ; Wang, Y ; Kujawski, M ; Kowolik, C ; Xin, H ; Chen, L ; Kretzner, L ; Yu, H ; Wilcox, W R ; Yen, Y ; Forman, S ; Jove, R</creatorcontrib><description>IL-6 and downstream JAK-dependent signaling pathways have critical roles in the pathophysiology of multiple myeloma (MM). We investigated the effects of a novel small-molecule JAK inhibitor (AZD1480) on IL-6/JAK signal transduction and its biological consequences on the human myeloma-derived cell lines U266 and Kms.11. At low micromolar concentrations, AZD1480 blocks cell proliferation and induces apoptosis of myeloma cell lines. These biological responses to AZD1480 are associated with concomitant inhibition of phosphorylation of JAK2, STAT3 and MAPK signaling proteins. In addition, there is inhibition of expression of STAT3 target genes, particularly Cyclin D2. Examination of a wider variety of myeloma cells (RPMI 8226, OPM-2, NCI-H929, Kms.18, MM1.S and IM-9), as well as primary myeloma cells, showed that AZD1480 has broad efficacy. In contrast, viability of normal peripheral blood (PB) mononuclear cells and CD138
+
cells derived from healthy controls was not significantly inhibited. Importantly, AZD1480 induces cell death of Kms.11 cells grown in the presence of HS-5 bone marrow (BM)-derived stromal cells and inhibits tumor growth in a Kms.11 xenograft mouse model, accompanied with inhibition of phospho-FGFR3, phospho-JAK2, phospho-STAT3 and Cyclin D2 levels. In sum, AZD1480 blocks proliferation, survival, FGFR3 and JAK/STAT3 signaling in myeloma cells cultured alone or cocultured with BM stromal cells, and
in vivo
. Thus, AZD1480 represents a potential new therapeutic agent for patients with MM.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/leu.2010.289</identifier><identifier>PMID: 21164517</identifier><identifier>CODEN: LEUKED</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/92/609 ; 692/699/67/1990/804 ; Animals ; Apoptosis ; Apoptosis - drug effects ; Biological and medical sciences ; Bone marrow ; Bone Marrow Cells - physiology ; Bone tumors ; Cancer Research ; Cancer therapies ; Cell culture ; Cell death ; Cell growth ; Cell Line, Tumor ; Cell proliferation ; Cell Proliferation - drug effects ; Cell survival ; Cell Survival - drug effects ; Cellular signal transduction ; Chemical compounds ; Clinical trials ; Critical Care Medicine ; Cyclin D2 ; Cyclin D2 - physiology ; Drug therapy ; Drugs ; Fibroblast growth factor receptors ; Gene expression ; Genetic aspects ; Health aspects ; Hematologic and hematopoietic diseases ; Hematology ; Humans ; Immunodeficiencies. Immunoglobulinopathies ; Immunoglobulinopathies ; Immunology ; Immunopathology ; Inhibitors ; Intensive ; Interleukin 6 ; Interleukin-6 - pharmacology ; Interleukins ; Internal Medicine ; Janus kinase 2 ; Janus Kinase 2 - antagonists & inhibitors ; Kinases ; Leukemia ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Leukocytes (mononuclear) ; MAP kinase ; MAP Kinase Signaling System - drug effects ; Medical sciences ; Medicine ; Medicine & Public Health ; Mice ; Multiple myeloma ; Multiple Myeloma - drug therapy ; Multiple Myeloma - pathology ; Oncology ; original-article ; Pathophysiology ; Peripheral blood mononuclear cells ; Pharmacology ; Phosphorylation ; Protein Kinase Inhibitors - pharmacology ; Pyrazoles - pharmacology ; Pyrimidines - pharmacology ; Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors ; Research centers ; Signal transduction ; Signal Transduction - drug effects ; Signaling ; Stat3 protein ; STAT3 Transcription Factor - antagonists & inhibitors ; Stromal cells ; Survival ; Tumor cell lines ; Xenografts ; Xenotransplantation</subject><ispartof>Leukemia, 2011-03, Vol.25 (3), p.538-550</ispartof><rights>Macmillan Publishers Limited 2011</rights><rights>2015 INIST-CNRS</rights><rights>COPYRIGHT 2011 Nature Publishing Group</rights><rights>Macmillan Publishers Limited 2011.</rights><rights>Copyright Nature Publishing Group Mar 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c702t-86523c768bda0e1ae6407af35874131b11ca7f3b19901942d86f8e0e42d84bff3</citedby><cites>FETCH-LOGICAL-c702t-86523c768bda0e1ae6407af35874131b11ca7f3b19901942d86f8e0e42d84bff3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/leu.2010.289$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/leu.2010.289$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23942584$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21164517$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Scuto, A</creatorcontrib><creatorcontrib>Krejci, P</creatorcontrib><creatorcontrib>Popplewell, L</creatorcontrib><creatorcontrib>Wu, J</creatorcontrib><creatorcontrib>Wang, Y</creatorcontrib><creatorcontrib>Kujawski, M</creatorcontrib><creatorcontrib>Kowolik, C</creatorcontrib><creatorcontrib>Xin, H</creatorcontrib><creatorcontrib>Chen, L</creatorcontrib><creatorcontrib>Kretzner, L</creatorcontrib><creatorcontrib>Yu, H</creatorcontrib><creatorcontrib>Wilcox, W R</creatorcontrib><creatorcontrib>Yen, Y</creatorcontrib><creatorcontrib>Forman, S</creatorcontrib><creatorcontrib>Jove, R</creatorcontrib><title>The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>IL-6 and downstream JAK-dependent signaling pathways have critical roles in the pathophysiology of multiple myeloma (MM). We investigated the effects of a novel small-molecule JAK inhibitor (AZD1480) on IL-6/JAK signal transduction and its biological consequences on the human myeloma-derived cell lines U266 and Kms.11. At low micromolar concentrations, AZD1480 blocks cell proliferation and induces apoptosis of myeloma cell lines. These biological responses to AZD1480 are associated with concomitant inhibition of phosphorylation of JAK2, STAT3 and MAPK signaling proteins. In addition, there is inhibition of expression of STAT3 target genes, particularly Cyclin D2. Examination of a wider variety of myeloma cells (RPMI 8226, OPM-2, NCI-H929, Kms.18, MM1.S and IM-9), as well as primary myeloma cells, showed that AZD1480 has broad efficacy. In contrast, viability of normal peripheral blood (PB) mononuclear cells and CD138
+
cells derived from healthy controls was not significantly inhibited. Importantly, AZD1480 induces cell death of Kms.11 cells grown in the presence of HS-5 bone marrow (BM)-derived stromal cells and inhibits tumor growth in a Kms.11 xenograft mouse model, accompanied with inhibition of phospho-FGFR3, phospho-JAK2, phospho-STAT3 and Cyclin D2 levels. In sum, AZD1480 blocks proliferation, survival, FGFR3 and JAK/STAT3 signaling in myeloma cells cultured alone or cocultured with BM stromal cells, and
in vivo
. Thus, AZD1480 represents a potential new therapeutic agent for patients with MM.</description><subject>631/92/609</subject><subject>692/699/67/1990/804</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Biological and medical sciences</subject><subject>Bone marrow</subject><subject>Bone Marrow Cells - physiology</subject><subject>Bone tumors</subject><subject>Cancer Research</subject><subject>Cancer therapies</subject><subject>Cell culture</subject><subject>Cell death</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell survival</subject><subject>Cell Survival - drug effects</subject><subject>Cellular signal transduction</subject><subject>Chemical compounds</subject><subject>Clinical trials</subject><subject>Critical Care Medicine</subject><subject>Cyclin D2</subject><subject>Cyclin D2 - physiology</subject><subject>Drug therapy</subject><subject>Drugs</subject><subject>Fibroblast growth factor receptors</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Hematology</subject><subject>Humans</subject><subject>Immunodeficiencies. Immunoglobulinopathies</subject><subject>Immunoglobulinopathies</subject><subject>Immunology</subject><subject>Immunopathology</subject><subject>Inhibitors</subject><subject>Intensive</subject><subject>Interleukin 6</subject><subject>Interleukin-6 - pharmacology</subject><subject>Interleukins</subject><subject>Internal Medicine</subject><subject>Janus kinase 2</subject><subject>Janus Kinase 2 - antagonists & inhibitors</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Leukocytes (mononuclear)</subject><subject>MAP kinase</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Multiple myeloma</subject><subject>Multiple Myeloma - drug therapy</subject><subject>Multiple Myeloma - pathology</subject><subject>Oncology</subject><subject>original-article</subject><subject>Pathophysiology</subject><subject>Peripheral blood mononuclear cells</subject><subject>Pharmacology</subject><subject>Phosphorylation</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyrimidines - pharmacology</subject><subject>Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors</subject><subject>Research centers</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Signaling</subject><subject>Stat3 protein</subject><subject>STAT3 Transcription Factor - antagonists & inhibitors</subject><subject>Stromal cells</subject><subject>Survival</subject><subject>Tumor cell lines</subject><subject>Xenografts</subject><subject>Xenotransplantation</subject><issn>0887-6924</issn><issn>1476-5551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqFks9v0zAUxyMEYl3hxhlZIOCyFP-IY-eCVA06fkxCgnLhYjmpk3g4drGTTrvzh-OsZV3REMohjt_nfV_ee98keYLgDEHCXxs1zDCMX5gX95IJylieUkrR_WQCOWdpXuDsKDkO4QLCMZg_TI4wQnlGEZskv5atAtZtlAEf55-Atq0ude88mH9_izIOQWlc9SOAr8v5kgBpV2BxtvhCQNCNlUbb5gR4FQbTx2PMBmFYr-NF0M4CV4N26KQF3ZUyrpOgUsaAxrvLvr2WCoPf6I00j5IHtTRBPd69p8m3xbvl6fv0_PPZh9P5eVoxiPuU5xSTiuW8XEmokFR5BpmsCeUsQwSVCFWS1aRERQFRkeEVz2uuoBpPWVnXZJq82equh7JTq0rZ3ksj1l530l8JJ7U4jFjdisZtBMEozxmKAq92At79HFToRafD2JW0yg1B8JwxwjjP_k_S-POcUxbJZ3-RF27wcbgjRIuCZLHrafL8XxCOm2QEx7p7qpFGCW1rF7uoxsJijimKchyNWrM7qPisVKcrZ1Wt4_1BwstbCa2Spm-DM0MflxwOwZMtWHkXglf1zWgRFKNZRTSrGM0qolkj_vT2Om7gP-6MwIsdIEMlTe2lrXTYcyQumV4PO91yIYZso_x-OncW_g3Mefz_</recordid><startdate>20110301</startdate><enddate>20110301</enddate><creator>Scuto, A</creator><creator>Krejci, P</creator><creator>Popplewell, L</creator><creator>Wu, J</creator><creator>Wang, Y</creator><creator>Kujawski, M</creator><creator>Kowolik, C</creator><creator>Xin, H</creator><creator>Chen, L</creator><creator>Kretzner, L</creator><creator>Yu, H</creator><creator>Wilcox, W R</creator><creator>Yen, Y</creator><creator>Forman, S</creator><creator>Jove, R</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>IQODW</scope><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>3V.</scope><scope>7QL</scope><scope>7RV</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20110301</creationdate><title>The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival</title><author>Scuto, A ; 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Myelofibrosis</topic><topic>Leukocytes (mononuclear)</topic><topic>MAP kinase</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Multiple myeloma</topic><topic>Multiple Myeloma - drug therapy</topic><topic>Multiple Myeloma - pathology</topic><topic>Oncology</topic><topic>original-article</topic><topic>Pathophysiology</topic><topic>Peripheral blood mononuclear cells</topic><topic>Pharmacology</topic><topic>Phosphorylation</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyrimidines - pharmacology</topic><topic>Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors</topic><topic>Research centers</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Signaling</topic><topic>Stat3 protein</topic><topic>STAT3 Transcription Factor - antagonists & inhibitors</topic><topic>Stromal cells</topic><topic>Survival</topic><topic>Tumor cell lines</topic><topic>Xenografts</topic><topic>Xenotransplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Scuto, A</creatorcontrib><creatorcontrib>Krejci, P</creatorcontrib><creatorcontrib>Popplewell, L</creatorcontrib><creatorcontrib>Wu, J</creatorcontrib><creatorcontrib>Wang, Y</creatorcontrib><creatorcontrib>Kujawski, M</creatorcontrib><creatorcontrib>Kowolik, C</creatorcontrib><creatorcontrib>Xin, H</creatorcontrib><creatorcontrib>Chen, L</creatorcontrib><creatorcontrib>Kretzner, L</creatorcontrib><creatorcontrib>Yu, H</creatorcontrib><creatorcontrib>Wilcox, W R</creatorcontrib><creatorcontrib>Yen, Y</creatorcontrib><creatorcontrib>Forman, S</creatorcontrib><creatorcontrib>Jove, R</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>ProQuest Nursing and Allied Health Journals</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection (Proquest)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection (Proquest) (PQ_SDU_P3)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Leukemia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Scuto, A</au><au>Krejci, P</au><au>Popplewell, L</au><au>Wu, J</au><au>Wang, Y</au><au>Kujawski, M</au><au>Kowolik, C</au><au>Xin, H</au><au>Chen, L</au><au>Kretzner, L</au><au>Yu, H</au><au>Wilcox, W R</au><au>Yen, Y</au><au>Forman, S</au><au>Jove, R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2011-03-01</date><risdate>2011</risdate><volume>25</volume><issue>3</issue><spage>538</spage><epage>550</epage><pages>538-550</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><coden>LEUKED</coden><abstract>IL-6 and downstream JAK-dependent signaling pathways have critical roles in the pathophysiology of multiple myeloma (MM). We investigated the effects of a novel small-molecule JAK inhibitor (AZD1480) on IL-6/JAK signal transduction and its biological consequences on the human myeloma-derived cell lines U266 and Kms.11. At low micromolar concentrations, AZD1480 blocks cell proliferation and induces apoptosis of myeloma cell lines. These biological responses to AZD1480 are associated with concomitant inhibition of phosphorylation of JAK2, STAT3 and MAPK signaling proteins. In addition, there is inhibition of expression of STAT3 target genes, particularly Cyclin D2. Examination of a wider variety of myeloma cells (RPMI 8226, OPM-2, NCI-H929, Kms.18, MM1.S and IM-9), as well as primary myeloma cells, showed that AZD1480 has broad efficacy. In contrast, viability of normal peripheral blood (PB) mononuclear cells and CD138
+
cells derived from healthy controls was not significantly inhibited. Importantly, AZD1480 induces cell death of Kms.11 cells grown in the presence of HS-5 bone marrow (BM)-derived stromal cells and inhibits tumor growth in a Kms.11 xenograft mouse model, accompanied with inhibition of phospho-FGFR3, phospho-JAK2, phospho-STAT3 and Cyclin D2 levels. In sum, AZD1480 blocks proliferation, survival, FGFR3 and JAK/STAT3 signaling in myeloma cells cultured alone or cocultured with BM stromal cells, and
in vivo
. Thus, AZD1480 represents a potential new therapeutic agent for patients with MM.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>21164517</pmid><doi>10.1038/leu.2010.289</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0887-6924 |
| ispartof | Leukemia, 2011-03, Vol.25 (3), p.538-550 |
| issn | 0887-6924 1476-5551 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3216671 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online; EZB Electronic Journals Library |
| subjects | 631/92/609 692/699/67/1990/804 Animals Apoptosis Apoptosis - drug effects Biological and medical sciences Bone marrow Bone Marrow Cells - physiology Bone tumors Cancer Research Cancer therapies Cell culture Cell death Cell growth Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Cell survival Cell Survival - drug effects Cellular signal transduction Chemical compounds Clinical trials Critical Care Medicine Cyclin D2 Cyclin D2 - physiology Drug therapy Drugs Fibroblast growth factor receptors Gene expression Genetic aspects Health aspects Hematologic and hematopoietic diseases Hematology Humans Immunodeficiencies. Immunoglobulinopathies Immunoglobulinopathies Immunology Immunopathology Inhibitors Intensive Interleukin 6 Interleukin-6 - pharmacology Interleukins Internal Medicine Janus kinase 2 Janus Kinase 2 - antagonists & inhibitors Kinases Leukemia Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Leukocytes (mononuclear) MAP kinase MAP Kinase Signaling System - drug effects Medical sciences Medicine Medicine & Public Health Mice Multiple myeloma Multiple Myeloma - drug therapy Multiple Myeloma - pathology Oncology original-article Pathophysiology Peripheral blood mononuclear cells Pharmacology Phosphorylation Protein Kinase Inhibitors - pharmacology Pyrazoles - pharmacology Pyrimidines - pharmacology Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors Research centers Signal transduction Signal Transduction - drug effects Signaling Stat3 protein STAT3 Transcription Factor - antagonists & inhibitors Stromal cells Survival Tumor cell lines Xenografts Xenotransplantation |
| title | The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival |
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