By inhibiting Src, verapamil and dasatinib overcome multidrug resistance via increased expression of Bim and decreased expressions of MDR1 and survivin in human multidrug-resistant myeloma cells
Abstract The calcium channel blocker verapamil inhibits the transport function of multidrug resistance protein 1 (MDR1). Although verapamil acts to reverse MDR in cancer cells, the underlying mechanism remains unclear. In the present study, we investigated the mechanism of reversing MDR by verapamil...
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| Veröffentlicht in: | Leukemia research 2014-01, Vol.38 (1), p.121-130 |
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| creator | Tsubaki, Masanobu Komai, Makiko Itoh, Tatsuki Imano, Motohiro Sakamoto, Kotaro Shimaoka, Hirotaka Takeda, Tomoya Ogawa, Naoki Mashimo, Kenji Fujiwara, Daiichiro Mukai, Junji Sakaguchi, Katsuhiko Satou, Takao Nishida, Shozo |
| description | Abstract The calcium channel blocker verapamil inhibits the transport function of multidrug resistance protein 1 (MDR1). Although verapamil acts to reverse MDR in cancer cells, the underlying mechanism remains unclear. In the present study, we investigated the mechanism of reversing MDR by verapamil in anti-cancer drug-resistant multiple myeloma (MM) cell lines. We found that verapamil suppresses MDR1 and survivin expressions and increases Bim expression via suppression of Src activation. Furthermore, dasatinib reversed the drug-resistance of the drug-resistant cell lines. These findings suggest that Src inhibitors are potentially useful as an anti-MDR agent for the treatment of malignant tumor cells. |
| doi_str_mv | 10.1016/j.leukres.2013.10.017 |
| format | Article |
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Although verapamil acts to reverse MDR in cancer cells, the underlying mechanism remains unclear. In the present study, we investigated the mechanism of reversing MDR by verapamil in anti-cancer drug-resistant multiple myeloma (MM) cell lines. We found that verapamil suppresses MDR1 and survivin expressions and increases Bim expression via suppression of Src activation. Furthermore, dasatinib reversed the drug-resistance of the drug-resistant cell lines. These findings suggest that Src inhibitors are potentially useful as an anti-MDR agent for the treatment of malignant tumor cells.</description><identifier>ISSN: 0145-2126</identifier><identifier>EISSN: 1873-5835</identifier><identifier>DOI: 10.1016/j.leukres.2013.10.017</identifier><identifier>PMID: 24239173</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; Apoptosis Regulatory Proteins - metabolism ; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism ; Bcl-2-Like Protein 11 ; Bim ; Blotting, Western ; Cell Line ; Cell Line, Tumor ; Cell Survival - drug effects ; Dasatinib ; Dexamethasone - pharmacology ; Down-Regulation - drug effects ; Doxorubicin - pharmacology ; Drug resistance ; Drug Resistance, Multiple - drug effects ; Drug Resistance, Neoplasm - drug effects ; Drug Synergism ; Enzyme Activation - drug effects ; Hematology, Oncology and Palliative Medicine ; Humans ; Inhibitor of Apoptosis Proteins - metabolism ; MDR1 ; Melphalan - pharmacology ; Membrane Proteins - metabolism ; Multiple myeloma ; Multiple Myeloma - metabolism ; Multiple Myeloma - pathology ; Protein Kinase Inhibitors - pharmacology ; Proto-Oncogene Proteins - metabolism ; Pyrimidines - pharmacology ; Src ; src-Family Kinases - metabolism ; Survivin ; Thiazoles - pharmacology ; Up-Regulation - drug effects ; Verapamil ; Verapamil - pharmacology</subject><ispartof>Leukemia research, 2014-01, Vol.38 (1), p.121-130</ispartof><rights>Elsevier Ltd</rights><rights>2013 Elsevier Ltd</rights><rights>Copyright © 2013 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c434t-de1cb2235fa2bfe0d0bfd3778eceac24e2665e466d4b28704e9fce156a1e86143</citedby><cites>FETCH-LOGICAL-c434t-de1cb2235fa2bfe0d0bfd3778eceac24e2665e466d4b28704e9fce156a1e86143</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.leukres.2013.10.017$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24239173$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tsubaki, Masanobu</creatorcontrib><creatorcontrib>Komai, Makiko</creatorcontrib><creatorcontrib>Itoh, Tatsuki</creatorcontrib><creatorcontrib>Imano, Motohiro</creatorcontrib><creatorcontrib>Sakamoto, Kotaro</creatorcontrib><creatorcontrib>Shimaoka, Hirotaka</creatorcontrib><creatorcontrib>Takeda, Tomoya</creatorcontrib><creatorcontrib>Ogawa, Naoki</creatorcontrib><creatorcontrib>Mashimo, Kenji</creatorcontrib><creatorcontrib>Fujiwara, Daiichiro</creatorcontrib><creatorcontrib>Mukai, Junji</creatorcontrib><creatorcontrib>Sakaguchi, Katsuhiko</creatorcontrib><creatorcontrib>Satou, Takao</creatorcontrib><creatorcontrib>Nishida, Shozo</creatorcontrib><title>By inhibiting Src, verapamil and dasatinib overcome multidrug resistance via increased expression of Bim and decreased expressions of MDR1 and survivin in human multidrug-resistant myeloma cells</title><title>Leukemia research</title><addtitle>Leuk Res</addtitle><description>Abstract The calcium channel blocker verapamil inhibits the transport function of multidrug resistance protein 1 (MDR1). Although verapamil acts to reverse MDR in cancer cells, the underlying mechanism remains unclear. In the present study, we investigated the mechanism of reversing MDR by verapamil in anti-cancer drug-resistant multiple myeloma (MM) cell lines. We found that verapamil suppresses MDR1 and survivin expressions and increases Bim expression via suppression of Src activation. Furthermore, dasatinib reversed the drug-resistance of the drug-resistant cell lines. These findings suggest that Src inhibitors are potentially useful as an anti-MDR agent for the treatment of malignant tumor cells.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis Regulatory Proteins - metabolism</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism</subject><subject>Bcl-2-Like Protein 11</subject><subject>Bim</subject><subject>Blotting, Western</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Dasatinib</subject><subject>Dexamethasone - pharmacology</subject><subject>Down-Regulation - drug effects</subject><subject>Doxorubicin - pharmacology</subject><subject>Drug resistance</subject><subject>Drug Resistance, Multiple - drug effects</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Synergism</subject><subject>Enzyme Activation - drug effects</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Humans</subject><subject>Inhibitor of Apoptosis Proteins - metabolism</subject><subject>MDR1</subject><subject>Melphalan - pharmacology</subject><subject>Membrane Proteins - metabolism</subject><subject>Multiple myeloma</subject><subject>Multiple Myeloma - metabolism</subject><subject>Multiple Myeloma - pathology</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Pyrimidines - pharmacology</subject><subject>Src</subject><subject>src-Family Kinases - metabolism</subject><subject>Survivin</subject><subject>Thiazoles - pharmacology</subject><subject>Up-Regulation - drug effects</subject><subject>Verapamil</subject><subject>Verapamil - pharmacology</subject><issn>0145-2126</issn><issn>1873-5835</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUstuFDEQtBCIbAKfAPKRA7P4OY8LiISnFIRE4Gx57J7Em_F4Y8-M2N_Ll-FhNyDBISdLXdVVVlUj9IySNSW0fLVZ9zBdR0hrRijPszWh1QO0onXFC1lz-RCtCBWyYJSVR-g4pQ0hRDa0eYyOmGC8oRVfodvTHXbDlWvd6IZLfBHNSzxD1FvtXY_1YLHVSWfMtThkwAQP2E_96GycLnH2d2nUgwE8O52VTASdwGL4uc1YcmHAocOnzu-14H88LYQv777R34w0xdnNbshS-GryevhrVtyZjdjvoA9eYwN9n56gR53uEzw9vCfox4f3388-FedfP34-e3teGMHFWFigpmWMy06ztgNiSdtZXlU1GNCGCWBlKUGUpRUtqysioOkMUFlqCnVJBT9BL_a62xhuJkij8i4tP9ADhCkpKgmpSskIuZ8qGlIJVnOWqXJPNTGkFKFT2-i8jjtFiVqaVht1aFotTS_j3HTee36wmFoP9s_WXbWZ8GZPgJzJ7CCqZBzkpqyLYEZlg7vX4vU_CqbPh2B0fw07SJswxSEHrqhKTBF1sZzbcm2U5wgqWvNfu6nWug</recordid><startdate>201401</startdate><enddate>201401</enddate><creator>Tsubaki, Masanobu</creator><creator>Komai, Makiko</creator><creator>Itoh, Tatsuki</creator><creator>Imano, Motohiro</creator><creator>Sakamoto, Kotaro</creator><creator>Shimaoka, Hirotaka</creator><creator>Takeda, Tomoya</creator><creator>Ogawa, Naoki</creator><creator>Mashimo, Kenji</creator><creator>Fujiwara, Daiichiro</creator><creator>Mukai, Junji</creator><creator>Sakaguchi, Katsuhiko</creator><creator>Satou, Takao</creator><creator>Nishida, Shozo</creator><general>Elsevier Ltd</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>7X8</scope><scope>7T5</scope><scope>H94</scope></search><sort><creationdate>201401</creationdate><title>By inhibiting Src, verapamil and dasatinib overcome multidrug resistance via increased expression of Bim and decreased expressions of MDR1 and survivin in human multidrug-resistant myeloma cells</title><author>Tsubaki, Masanobu ; Komai, Makiko ; Itoh, Tatsuki ; Imano, Motohiro ; Sakamoto, Kotaro ; Shimaoka, Hirotaka ; Takeda, Tomoya ; Ogawa, Naoki ; Mashimo, Kenji ; Fujiwara, Daiichiro ; Mukai, Junji ; Sakaguchi, Katsuhiko ; Satou, Takao ; Nishida, Shozo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c434t-de1cb2235fa2bfe0d0bfd3778eceac24e2665e466d4b28704e9fce156a1e86143</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis Regulatory Proteins - metabolism</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism</topic><topic>Bcl-2-Like Protein 11</topic><topic>Bim</topic><topic>Blotting, Western</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Dasatinib</topic><topic>Dexamethasone - pharmacology</topic><topic>Down-Regulation - drug effects</topic><topic>Doxorubicin - pharmacology</topic><topic>Drug resistance</topic><topic>Drug Resistance, Multiple - drug effects</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Drug Synergism</topic><topic>Enzyme Activation - drug effects</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>Humans</topic><topic>Inhibitor of Apoptosis Proteins - metabolism</topic><topic>MDR1</topic><topic>Melphalan - pharmacology</topic><topic>Membrane Proteins - metabolism</topic><topic>Multiple myeloma</topic><topic>Multiple Myeloma - metabolism</topic><topic>Multiple Myeloma - pathology</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Pyrimidines - pharmacology</topic><topic>Src</topic><topic>src-Family Kinases - metabolism</topic><topic>Survivin</topic><topic>Thiazoles - pharmacology</topic><topic>Up-Regulation - drug effects</topic><topic>Verapamil</topic><topic>Verapamil - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tsubaki, Masanobu</creatorcontrib><creatorcontrib>Komai, Makiko</creatorcontrib><creatorcontrib>Itoh, Tatsuki</creatorcontrib><creatorcontrib>Imano, Motohiro</creatorcontrib><creatorcontrib>Sakamoto, Kotaro</creatorcontrib><creatorcontrib>Shimaoka, Hirotaka</creatorcontrib><creatorcontrib>Takeda, Tomoya</creatorcontrib><creatorcontrib>Ogawa, Naoki</creatorcontrib><creatorcontrib>Mashimo, Kenji</creatorcontrib><creatorcontrib>Fujiwara, Daiichiro</creatorcontrib><creatorcontrib>Mukai, Junji</creatorcontrib><creatorcontrib>Sakaguchi, Katsuhiko</creatorcontrib><creatorcontrib>Satou, Takao</creatorcontrib><creatorcontrib>Nishida, Shozo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Leukemia research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tsubaki, Masanobu</au><au>Komai, Makiko</au><au>Itoh, Tatsuki</au><au>Imano, Motohiro</au><au>Sakamoto, Kotaro</au><au>Shimaoka, Hirotaka</au><au>Takeda, Tomoya</au><au>Ogawa, Naoki</au><au>Mashimo, Kenji</au><au>Fujiwara, Daiichiro</au><au>Mukai, Junji</au><au>Sakaguchi, Katsuhiko</au><au>Satou, Takao</au><au>Nishida, Shozo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>By inhibiting Src, verapamil and dasatinib overcome multidrug resistance via increased expression of Bim and decreased expressions of MDR1 and survivin in human multidrug-resistant myeloma cells</atitle><jtitle>Leukemia research</jtitle><addtitle>Leuk Res</addtitle><date>2014-01</date><risdate>2014</risdate><volume>38</volume><issue>1</issue><spage>121</spage><epage>130</epage><pages>121-130</pages><issn>0145-2126</issn><eissn>1873-5835</eissn><abstract>Abstract The calcium channel blocker verapamil inhibits the transport function of multidrug resistance protein 1 (MDR1). Although verapamil acts to reverse MDR in cancer cells, the underlying mechanism remains unclear. In the present study, we investigated the mechanism of reversing MDR by verapamil in anti-cancer drug-resistant multiple myeloma (MM) cell lines. We found that verapamil suppresses MDR1 and survivin expressions and increases Bim expression via suppression of Src activation. Furthermore, dasatinib reversed the drug-resistance of the drug-resistant cell lines. These findings suggest that Src inhibitors are potentially useful as an anti-MDR agent for the treatment of malignant tumor cells.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>24239173</pmid><doi>10.1016/j.leukres.2013.10.017</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Leukemia research, 2014-01, Vol.38 (1), p.121-130 |
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| subjects | Animals Antineoplastic Agents - pharmacology Apoptosis Regulatory Proteins - metabolism ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism Bcl-2-Like Protein 11 Bim Blotting, Western Cell Line Cell Line, Tumor Cell Survival - drug effects Dasatinib Dexamethasone - pharmacology Down-Regulation - drug effects Doxorubicin - pharmacology Drug resistance Drug Resistance, Multiple - drug effects Drug Resistance, Neoplasm - drug effects Drug Synergism Enzyme Activation - drug effects Hematology, Oncology and Palliative Medicine Humans Inhibitor of Apoptosis Proteins - metabolism MDR1 Melphalan - pharmacology Membrane Proteins - metabolism Multiple myeloma Multiple Myeloma - metabolism Multiple Myeloma - pathology Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins - metabolism Pyrimidines - pharmacology Src src-Family Kinases - metabolism Survivin Thiazoles - pharmacology Up-Regulation - drug effects Verapamil Verapamil - pharmacology |
| title | By inhibiting Src, verapamil and dasatinib overcome multidrug resistance via increased expression of Bim and decreased expressions of MDR1 and survivin in human multidrug-resistant myeloma cells |
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