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ERBB and P‐glycoprotein inhibitors break resistance in relapsed neuroblastoma models through P‐glycoprotein
Chemotherapy resistance is a persistent clinical problem in relapsed high‐risk neuroblastomas. We tested a panel of 15 drugs for sensitization of neuroblastoma cells to the conventional chemotherapeutic vincristine, identifying tariquidar, an inhibitor of the transmembrane pump P‐glycoprotein (P‐gp/...
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Published in: | Molecular oncology 2023-01, Vol.17 (1), p.37-58 |
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description | Chemotherapy resistance is a persistent clinical problem in relapsed high‐risk neuroblastomas. We tested a panel of 15 drugs for sensitization of neuroblastoma cells to the conventional chemotherapeutic vincristine, identifying tariquidar, an inhibitor of the transmembrane pump P‐glycoprotein (P‐gp/ABCB1), and the ERBB family inhibitor afatinib as the top resistance breakers. Both compounds were efficient in sensitizing neuroblastoma cells to vincristine in trypan blue exclusion assays and in inducing apoptotic cell death. The evaluation of ERBB signaling revealed no functional inhibition, that is, dephosphorylation of the downstream pathways upon afatinib treatment but direct off‐target interference with P‐gp function. Depletion of ABCB1, but not ERRB4, sensitized cells to vincristine treatment. P‐gp inhibition substantially broke vincristine resistance in vitro and in vivo (zebrafish embryo xenograft). The analysis of gene expression datasets of more than 50 different neuroblastoma cell lines (primary and relapsed) and more than 160 neuroblastoma patient samples from the pediatric precision medicine platform INFORM (Individualized Therapy For Relapsed Malignancies in Childhood) confirmed a pivotal role of P‐gp specifically in neuroblastoma resistance at relapse, while the ERBB family appears to play a minor part.
Chemotherapy resistance is a clinical problem in relapsed neuroblastomas (NBs). With a vincristine (VCR, yellow symbol) resistant model (A), we identified tariquidar (green), an inhibitor of the efflux pump P‐gp/ABCB1, and afatinib (orange), an ERBB inhibitor, as resistance breaker (B). The comprehensive analysis of ERBB4 and P‐gp/ABCB1 expression and function (C), revealed that both drugs act through P‐gp inhibition (D). |
doi_str_mv | 10.1002/1878-0261.13318 |
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Chemotherapy resistance is a clinical problem in relapsed neuroblastomas (NBs). With a vincristine (VCR, yellow symbol) resistant model (A), we identified tariquidar (green), an inhibitor of the efflux pump P‐gp/ABCB1, and afatinib (orange), an ERBB inhibitor, as resistance breaker (B). The comprehensive analysis of ERBB4 and P‐gp/ABCB1 expression and function (C), revealed that both drugs act through P‐gp inhibition (D).</description><identifier>ISSN: 1574-7891</identifier><identifier>EISSN: 1878-0261</identifier><identifier>DOI: 10.1002/1878-0261.13318</identifier><identifier>PMID: 36181342</identifier><language>eng</language><publisher>United States: John Wiley & Sons, Inc</publisher><subject>Afatinib ; Analysis ; Animals ; Antimitotic agents ; Antineoplastic agents ; Apoptosis ; apoptotic cell death ; ATP Binding Cassette Transporter, Subfamily B - genetics ; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics ; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism ; Cancer ; Cancer therapies ; Cell culture ; Cell death ; Cell Line, Tumor ; Cell lines ; Chemoresistance ; Chemotherapy ; chemotherapy resistance ; Children ; Dephosphorylation ; Drug resistance ; Drug Resistance, Neoplasm ; ErbB protein ; ErbB Receptors - metabolism ; Gene expression ; Glycoproteins ; Humans ; Kinases ; Malignancy ; Medical prognosis ; Metabolism ; Microorganisms ; Neuroblastoma ; Neuroblastoma - genetics ; Neuroblastoma cells ; off‐target ; Patients ; pediatric patient samples ; Pediatrics ; Precision medicine ; Recurrence ; Scientific equipment and supplies industry ; Tumors ; Vincristine ; Vincristine - pharmacology ; Xenografts ; Zebrafish - metabolism ; zebrafish xenograft model</subject><ispartof>Molecular oncology, 2023-01, Vol.17 (1), p.37-58</ispartof><rights>2022 The Authors. published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.</rights><rights>2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.</rights><rights>COPYRIGHT 2023 John Wiley & Sons, Inc.</rights><rights>2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5688-1125d90dd1a91f6bbccdab011fd28679f01500d06077aada71ea5c6fac815c1f3</citedby><cites>FETCH-LOGICAL-c5688-1125d90dd1a91f6bbccdab011fd28679f01500d06077aada71ea5c6fac815c1f3</cites><orcidid>0000-0002-0827-2356</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2760684788/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2760684788?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,11541,25731,27901,27902,36989,44566,46027,46451,53766,53768,74869</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36181342$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rösch, Lisa</creatorcontrib><creatorcontrib>Herter, Sonja</creatorcontrib><creatorcontrib>Najafi, Sara</creatorcontrib><creatorcontrib>Ridinger, Johannes</creatorcontrib><creatorcontrib>Peterziel, Heike</creatorcontrib><creatorcontrib>Cinatl, Jindrich</creatorcontrib><creatorcontrib>Jones, David T. W.</creatorcontrib><creatorcontrib>Michaelis, Martin</creatorcontrib><creatorcontrib>Witt, Olaf</creatorcontrib><creatorcontrib>Oehme, Ina</creatorcontrib><title>ERBB and P‐glycoprotein inhibitors break resistance in relapsed neuroblastoma models through P‐glycoprotein</title><title>Molecular oncology</title><addtitle>Mol Oncol</addtitle><description>Chemotherapy resistance is a persistent clinical problem in relapsed high‐risk neuroblastomas. We tested a panel of 15 drugs for sensitization of neuroblastoma cells to the conventional chemotherapeutic vincristine, identifying tariquidar, an inhibitor of the transmembrane pump P‐glycoprotein (P‐gp/ABCB1), and the ERBB family inhibitor afatinib as the top resistance breakers. Both compounds were efficient in sensitizing neuroblastoma cells to vincristine in trypan blue exclusion assays and in inducing apoptotic cell death. The evaluation of ERBB signaling revealed no functional inhibition, that is, dephosphorylation of the downstream pathways upon afatinib treatment but direct off‐target interference with P‐gp function. Depletion of ABCB1, but not ERRB4, sensitized cells to vincristine treatment. P‐gp inhibition substantially broke vincristine resistance in vitro and in vivo (zebrafish embryo xenograft). The analysis of gene expression datasets of more than 50 different neuroblastoma cell lines (primary and relapsed) and more than 160 neuroblastoma patient samples from the pediatric precision medicine platform INFORM (Individualized Therapy For Relapsed Malignancies in Childhood) confirmed a pivotal role of P‐gp specifically in neuroblastoma resistance at relapse, while the ERBB family appears to play a minor part.
Chemotherapy resistance is a clinical problem in relapsed neuroblastomas (NBs). With a vincristine (VCR, yellow symbol) resistant model (A), we identified tariquidar (green), an inhibitor of the efflux pump P‐gp/ABCB1, and afatinib (orange), an ERBB inhibitor, as resistance breaker (B). The comprehensive analysis of ERBB4 and P‐gp/ABCB1 expression and function (C), revealed that both drugs act through P‐gp inhibition (D).</description><subject>Afatinib</subject><subject>Analysis</subject><subject>Animals</subject><subject>Antimitotic agents</subject><subject>Antineoplastic agents</subject><subject>Apoptosis</subject><subject>apoptotic cell death</subject><subject>ATP Binding Cassette Transporter, Subfamily B - genetics</subject><subject>ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics</subject><subject>ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cell culture</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Cell lines</subject><subject>Chemoresistance</subject><subject>Chemotherapy</subject><subject>chemotherapy resistance</subject><subject>Children</subject><subject>Dephosphorylation</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm</subject><subject>ErbB protein</subject><subject>ErbB Receptors - metabolism</subject><subject>Gene expression</subject><subject>Glycoproteins</subject><subject>Humans</subject><subject>Kinases</subject><subject>Malignancy</subject><subject>Medical prognosis</subject><subject>Metabolism</subject><subject>Microorganisms</subject><subject>Neuroblastoma</subject><subject>Neuroblastoma - genetics</subject><subject>Neuroblastoma cells</subject><subject>off‐target</subject><subject>Patients</subject><subject>pediatric patient samples</subject><subject>Pediatrics</subject><subject>Precision medicine</subject><subject>Recurrence</subject><subject>Scientific equipment and supplies industry</subject><subject>Tumors</subject><subject>Vincristine</subject><subject>Vincristine - pharmacology</subject><subject>Xenografts</subject><subject>Zebrafish - metabolism</subject><subject>zebrafish xenograft model</subject><issn>1574-7891</issn><issn>1878-0261</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqFks9u1DAQxiMEoqVw5oYicd6tJ4n_XZDaqkClRUUIztbEdrJeknixs0V76yP0GXkSvE1ZWIGEfLBn5pufZ6Qvy14CmQMhxSkILmakYDCHsgTxKDveZx6nN-XVjAsJR9mzGFeEUCaZfJodlQwElFVxnPnLT-fnOQ4m__jj9q7tttqvgx-tG3I3LF3tRh9iXgeLX_Ngo4sjDtqmWoo6XEdr8sFugq87jKPvMe-9sV3Mx2Xwm3b5F_V59qTBLtoXD_dJ9uXt5eeL97PF9buri7PFTFMmxAygoEYSYwAlNKyutTZYE4DGFIJx2RCghBjCCOeIBjlYpJo1qAVQDU15kl1NXONxpdbB9Ri2yqNT9wkfWoVhdLqzimhNrNQWTQGVkaaW1NBKWyspYbrExHozsdaburdG22EM2B1ADyuDW6rW3ygpoBAlTYDXD4Dgv21sHNXKb8KQ9lcFZ4SJigvxW9VimsoNjU8w3buo1RmvZCU5pTKp5v9QpWNs77QfbONS_qDhdGrQwccYbLMfHIjamUjtLKN2llH3Jkodr_7cd6__5ZokYJPge_pr-z-e-nC9KCbyT6Wb1UM</recordid><startdate>202301</startdate><enddate>202301</enddate><creator>Rösch, Lisa</creator><creator>Herter, Sonja</creator><creator>Najafi, Sara</creator><creator>Ridinger, Johannes</creator><creator>Peterziel, Heike</creator><creator>Cinatl, Jindrich</creator><creator>Jones, David T. W.</creator><creator>Michaelis, Martin</creator><creator>Witt, Olaf</creator><creator>Oehme, Ina</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><general>Wiley</general><scope>24P</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>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-0827-2356</orcidid></search><sort><creationdate>202301</creationdate><title>ERBB and P‐glycoprotein inhibitors break resistance in relapsed neuroblastoma models through P‐glycoprotein</title><author>Rösch, Lisa ; Herter, Sonja ; Najafi, Sara ; Ridinger, Johannes ; Peterziel, Heike ; Cinatl, Jindrich ; Jones, David T. W. ; Michaelis, Martin ; Witt, Olaf ; Oehme, Ina</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5688-1125d90dd1a91f6bbccdab011fd28679f01500d06077aada71ea5c6fac815c1f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Afatinib</topic><topic>Analysis</topic><topic>Animals</topic><topic>Antimitotic agents</topic><topic>Antineoplastic agents</topic><topic>Apoptosis</topic><topic>apoptotic cell death</topic><topic>ATP Binding Cassette Transporter, Subfamily B - genetics</topic><topic>ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics</topic><topic>ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Cell culture</topic><topic>Cell death</topic><topic>Cell Line, Tumor</topic><topic>Cell lines</topic><topic>Chemoresistance</topic><topic>Chemotherapy</topic><topic>chemotherapy resistance</topic><topic>Children</topic><topic>Dephosphorylation</topic><topic>Drug resistance</topic><topic>Drug Resistance, Neoplasm</topic><topic>ErbB protein</topic><topic>ErbB Receptors - metabolism</topic><topic>Gene expression</topic><topic>Glycoproteins</topic><topic>Humans</topic><topic>Kinases</topic><topic>Malignancy</topic><topic>Medical prognosis</topic><topic>Metabolism</topic><topic>Microorganisms</topic><topic>Neuroblastoma</topic><topic>Neuroblastoma - genetics</topic><topic>Neuroblastoma cells</topic><topic>off‐target</topic><topic>Patients</topic><topic>pediatric patient samples</topic><topic>Pediatrics</topic><topic>Precision medicine</topic><topic>Recurrence</topic><topic>Scientific equipment and supplies industry</topic><topic>Tumors</topic><topic>Vincristine</topic><topic>Vincristine - pharmacology</topic><topic>Xenografts</topic><topic>Zebrafish - metabolism</topic><topic>zebrafish xenograft model</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rösch, Lisa</creatorcontrib><creatorcontrib>Herter, Sonja</creatorcontrib><creatorcontrib>Najafi, Sara</creatorcontrib><creatorcontrib>Ridinger, Johannes</creatorcontrib><creatorcontrib>Peterziel, Heike</creatorcontrib><creatorcontrib>Cinatl, Jindrich</creatorcontrib><creatorcontrib>Jones, David T. W.</creatorcontrib><creatorcontrib>Michaelis, Martin</creatorcontrib><creatorcontrib>Witt, Olaf</creatorcontrib><creatorcontrib>Oehme, Ina</creatorcontrib><collection>Wiley Open Access</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 SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>Biological Sciences</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</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>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Molecular oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rösch, Lisa</au><au>Herter, Sonja</au><au>Najafi, Sara</au><au>Ridinger, Johannes</au><au>Peterziel, Heike</au><au>Cinatl, Jindrich</au><au>Jones, David T. W.</au><au>Michaelis, Martin</au><au>Witt, Olaf</au><au>Oehme, Ina</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ERBB and P‐glycoprotein inhibitors break resistance in relapsed neuroblastoma models through P‐glycoprotein</atitle><jtitle>Molecular oncology</jtitle><addtitle>Mol Oncol</addtitle><date>2023-01</date><risdate>2023</risdate><volume>17</volume><issue>1</issue><spage>37</spage><epage>58</epage><pages>37-58</pages><issn>1574-7891</issn><eissn>1878-0261</eissn><abstract>Chemotherapy resistance is a persistent clinical problem in relapsed high‐risk neuroblastomas. We tested a panel of 15 drugs for sensitization of neuroblastoma cells to the conventional chemotherapeutic vincristine, identifying tariquidar, an inhibitor of the transmembrane pump P‐glycoprotein (P‐gp/ABCB1), and the ERBB family inhibitor afatinib as the top resistance breakers. Both compounds were efficient in sensitizing neuroblastoma cells to vincristine in trypan blue exclusion assays and in inducing apoptotic cell death. The evaluation of ERBB signaling revealed no functional inhibition, that is, dephosphorylation of the downstream pathways upon afatinib treatment but direct off‐target interference with P‐gp function. Depletion of ABCB1, but not ERRB4, sensitized cells to vincristine treatment. P‐gp inhibition substantially broke vincristine resistance in vitro and in vivo (zebrafish embryo xenograft). The analysis of gene expression datasets of more than 50 different neuroblastoma cell lines (primary and relapsed) and more than 160 neuroblastoma patient samples from the pediatric precision medicine platform INFORM (Individualized Therapy For Relapsed Malignancies in Childhood) confirmed a pivotal role of P‐gp specifically in neuroblastoma resistance at relapse, while the ERBB family appears to play a minor part.
Chemotherapy resistance is a clinical problem in relapsed neuroblastomas (NBs). With a vincristine (VCR, yellow symbol) resistant model (A), we identified tariquidar (green), an inhibitor of the efflux pump P‐gp/ABCB1, and afatinib (orange), an ERBB inhibitor, as resistance breaker (B). The comprehensive analysis of ERBB4 and P‐gp/ABCB1 expression and function (C), revealed that both drugs act through P‐gp inhibition (D).</abstract><cop>United States</cop><pub>John Wiley & Sons, Inc</pub><pmid>36181342</pmid><doi>10.1002/1878-0261.13318</doi><tpages>58</tpages><orcidid>https://orcid.org/0000-0002-0827-2356</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Afatinib Analysis Animals Antimitotic agents Antineoplastic agents Apoptosis apoptotic cell death ATP Binding Cassette Transporter, Subfamily B - genetics ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism Cancer Cancer therapies Cell culture Cell death Cell Line, Tumor Cell lines Chemoresistance Chemotherapy chemotherapy resistance Children Dephosphorylation Drug resistance Drug Resistance, Neoplasm ErbB protein ErbB Receptors - metabolism Gene expression Glycoproteins Humans Kinases Malignancy Medical prognosis Metabolism Microorganisms Neuroblastoma Neuroblastoma - genetics Neuroblastoma cells off‐target Patients pediatric patient samples Pediatrics Precision medicine Recurrence Scientific equipment and supplies industry Tumors Vincristine Vincristine - pharmacology Xenografts Zebrafish - metabolism zebrafish xenograft model |
title | ERBB and P‐glycoprotein inhibitors break resistance in relapsed neuroblastoma models through P‐glycoprotein |
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