Folates provoke cellular efflux and drug resistance of substrates of the multidrug resistance protein 1 (MRP1)
Cellular folate concentration was earlier reported to be a critical factor in the activity and expression of the multidrug resistance protein MRP1 (ABCC1). Since MRP1 mediates resistance to a variety of therapeutic drugs, we investigated whether the cellular folate concentration influences the MRP1-...
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| Veröffentlicht in: | Cancer chemotherapy and pharmacology 2014-05, Vol.73 (5), p.911-917 |
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| container_title | Cancer chemotherapy and pharmacology |
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| creator | Hooijberg, Jan Hendrik Jansen, Gerrit Kathmann, Ietje Pieters, Rob Laan, Adrie C. van Zantwijk, Ina Kaspers, Gertjan J. L. Peters, Godefridus J. |
| description | Cellular folate concentration was earlier reported to be a critical factor in the activity and expression of the multidrug resistance protein MRP1 (ABCC1). Since MRP1 mediates resistance to a variety of therapeutic drugs, we investigated whether the cellular folate concentration influences the MRP1-mediated cellular resistance against drugs. As a model system, we used the human ovarian carcinoma cell line 2008wt, and its stably MRP1/ABCC1-transfected subline 2008/MRP1. These cell types have a moderate and high expression of MRP1, respectively. In folate-deprived 2008/MRP1 cells, the MRP1-mediated efflux of its model substrate calcein decreased to ~55 % of the initial efflux rate under folate-rich conditions. In 2008wt cells, only a small decrease in efflux was observed. Folate depletion for 5–10 days markedly increased (~500 %) cellular steady-state accumulation of calcein in 2008/MRP1 cells and moderately in 2008wt cells. A subsequent short (24 h) exposure to 2.3 μM
l
-leucovorin decreased calcein levels again in MRP1-overexpressing cells. Folate deprivation markedly increased growth inhibitory effects of the established MRP1 substrates daunorubicin (~twofold), doxorubicin (~fivefold), and methotrexate (~83-fold) in MRP1-overexpressing cells, proportional to MRP1 expression. In conclusion, this study demonstrates that increased cellular folate concentrations induce MRP1/ABCC1-related drug efflux and drug resistance. These results have important implications in the understanding of the role of MRP1 and its homologs in clinical drug resistance. |
| doi_str_mv | 10.1007/s00280-014-2421-0 |
| format | Article |
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l
-leucovorin decreased calcein levels again in MRP1-overexpressing cells. Folate deprivation markedly increased growth inhibitory effects of the established MRP1 substrates daunorubicin (~twofold), doxorubicin (~fivefold), and methotrexate (~83-fold) in MRP1-overexpressing cells, proportional to MRP1 expression. In conclusion, this study demonstrates that increased cellular folate concentrations induce MRP1/ABCC1-related drug efflux and drug resistance. These results have important implications in the understanding of the role of MRP1 and its homologs in clinical drug resistance.</description><identifier>ISSN: 0344-5704</identifier><identifier>EISSN: 1432-0843</identifier><identifier>DOI: 10.1007/s00280-014-2421-0</identifier><identifier>PMID: 24595806</identifier><identifier>CODEN: CCPHDZ</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Antineoplastic agents ; Biological and medical sciences ; Biological Transport ; Cancer Research ; Cell Line, Tumor ; Drug Resistance - drug effects ; Folic Acid - metabolism ; Humans ; Medical sciences ; Medicine ; Medicine & Public Health ; Methotrexate - pharmacology ; Multidrug Resistance-Associated Proteins - drug effects ; Multidrug Resistance-Associated Proteins - metabolism ; Oncology ; Original Article ; Pharmacology. Drug treatments ; Pharmacology/Toxicology</subject><ispartof>Cancer chemotherapy and pharmacology, 2014-05, Vol.73 (5), p.911-917</ispartof><rights>Springer-Verlag Berlin Heidelberg 2014</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c445t-e4cbb93bbdfbdadf7d4ba2fedc8a62d9cd926cdfc3f1c7cf78ba1f9878ee06ab3</citedby><cites>FETCH-LOGICAL-c445t-e4cbb93bbdfbdadf7d4ba2fedc8a62d9cd926cdfc3f1c7cf78ba1f9878ee06ab3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00280-014-2421-0$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00280-014-2421-0$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28598502$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24595806$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hooijberg, Jan Hendrik</creatorcontrib><creatorcontrib>Jansen, Gerrit</creatorcontrib><creatorcontrib>Kathmann, Ietje</creatorcontrib><creatorcontrib>Pieters, Rob</creatorcontrib><creatorcontrib>Laan, Adrie C.</creatorcontrib><creatorcontrib>van Zantwijk, Ina</creatorcontrib><creatorcontrib>Kaspers, Gertjan J. L.</creatorcontrib><creatorcontrib>Peters, Godefridus J.</creatorcontrib><title>Folates provoke cellular efflux and drug resistance of substrates of the multidrug resistance protein 1 (MRP1)</title><title>Cancer chemotherapy and pharmacology</title><addtitle>Cancer Chemother Pharmacol</addtitle><addtitle>Cancer Chemother Pharmacol</addtitle><description>Cellular folate concentration was earlier reported to be a critical factor in the activity and expression of the multidrug resistance protein MRP1 (ABCC1). Since MRP1 mediates resistance to a variety of therapeutic drugs, we investigated whether the cellular folate concentration influences the MRP1-mediated cellular resistance against drugs. As a model system, we used the human ovarian carcinoma cell line 2008wt, and its stably MRP1/ABCC1-transfected subline 2008/MRP1. These cell types have a moderate and high expression of MRP1, respectively. In folate-deprived 2008/MRP1 cells, the MRP1-mediated efflux of its model substrate calcein decreased to ~55 % of the initial efflux rate under folate-rich conditions. In 2008wt cells, only a small decrease in efflux was observed. Folate depletion for 5–10 days markedly increased (~500 %) cellular steady-state accumulation of calcein in 2008/MRP1 cells and moderately in 2008wt cells. A subsequent short (24 h) exposure to 2.3 μM
l
-leucovorin decreased calcein levels again in MRP1-overexpressing cells. Folate deprivation markedly increased growth inhibitory effects of the established MRP1 substrates daunorubicin (~twofold), doxorubicin (~fivefold), and methotrexate (~83-fold) in MRP1-overexpressing cells, proportional to MRP1 expression. In conclusion, this study demonstrates that increased cellular folate concentrations induce MRP1/ABCC1-related drug efflux and drug resistance. These results have important implications in the understanding of the role of MRP1 and its homologs in clinical drug resistance.</description><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Biological Transport</subject><subject>Cancer Research</subject><subject>Cell Line, Tumor</subject><subject>Drug Resistance - drug effects</subject><subject>Folic Acid - metabolism</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Methotrexate - pharmacology</subject><subject>Multidrug Resistance-Associated Proteins - drug effects</subject><subject>Multidrug Resistance-Associated Proteins - metabolism</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Pharmacology. Drug treatments</subject><subject>Pharmacology/Toxicology</subject><issn>0344-5704</issn><issn>1432-0843</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp1kd1rFDEUxYModrv6B_giARHqw-jNx-xkHkuxVagoos8hHzd16uxMzZ2I_vdmu-sHBZ9CyO_cnHsOY08EvBQA3SsCkAYaELqRWooG7rGV0Eo2YLS6z1agtG7aDvQROya6BgAtlHrIjqRu-9bAZsWm83l0CxK_yfP3-SvygONYRpc5pjSWH9xNkcdcrnhGGmhxU0A-J07F05JvlfW2fEG-LeMy3CXr1AWHiQt-8u7jB_HiEXuQ3Ej4-HCu2efz15_O3jSX7y_enp1eNkHrdmlQB-975X1MPrqYuqi9kwljMG4jYx9iLzchpqCSCF1InfFOpN50BhE2zqs1O9nPrQa-FaTFbgfareYmnAtZ0YreqF7WtNbs2R30ei55qu5uqZqw6tpKiT0V8kyUMdmbPGxd_mkF2F0Zdl-GrWXYXRkWqubpYXLxW4x_FL_Tr8DzA-AouDHlmtlAfznT9qYFWTm556g-TVeY_7H4399_AX-Yo58</recordid><startdate>20140501</startdate><enddate>20140501</enddate><creator>Hooijberg, Jan Hendrik</creator><creator>Jansen, Gerrit</creator><creator>Kathmann, Ietje</creator><creator>Pieters, Rob</creator><creator>Laan, Adrie C.</creator><creator>van Zantwijk, Ina</creator><creator>Kaspers, Gertjan J. 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L. ; Peters, Godefridus J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c445t-e4cbb93bbdfbdadf7d4ba2fedc8a62d9cd926cdfc3f1c7cf78ba1f9878ee06ab3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Biological Transport</topic><topic>Cancer Research</topic><topic>Cell Line, Tumor</topic><topic>Drug Resistance - drug effects</topic><topic>Folic Acid - metabolism</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Methotrexate - pharmacology</topic><topic>Multidrug Resistance-Associated Proteins - drug effects</topic><topic>Multidrug Resistance-Associated Proteins - metabolism</topic><topic>Oncology</topic><topic>Original Article</topic><topic>Pharmacology. Drug treatments</topic><topic>Pharmacology/Toxicology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hooijberg, Jan Hendrik</creatorcontrib><creatorcontrib>Jansen, Gerrit</creatorcontrib><creatorcontrib>Kathmann, Ietje</creatorcontrib><creatorcontrib>Pieters, Rob</creatorcontrib><creatorcontrib>Laan, Adrie C.</creatorcontrib><creatorcontrib>van Zantwijk, Ina</creatorcontrib><creatorcontrib>Kaspers, Gertjan J. 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L.</au><au>Peters, Godefridus J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Folates provoke cellular efflux and drug resistance of substrates of the multidrug resistance protein 1 (MRP1)</atitle><jtitle>Cancer chemotherapy and pharmacology</jtitle><stitle>Cancer Chemother Pharmacol</stitle><addtitle>Cancer Chemother Pharmacol</addtitle><date>2014-05-01</date><risdate>2014</risdate><volume>73</volume><issue>5</issue><spage>911</spage><epage>917</epage><pages>911-917</pages><issn>0344-5704</issn><eissn>1432-0843</eissn><coden>CCPHDZ</coden><abstract>Cellular folate concentration was earlier reported to be a critical factor in the activity and expression of the multidrug resistance protein MRP1 (ABCC1). Since MRP1 mediates resistance to a variety of therapeutic drugs, we investigated whether the cellular folate concentration influences the MRP1-mediated cellular resistance against drugs. As a model system, we used the human ovarian carcinoma cell line 2008wt, and its stably MRP1/ABCC1-transfected subline 2008/MRP1. These cell types have a moderate and high expression of MRP1, respectively. In folate-deprived 2008/MRP1 cells, the MRP1-mediated efflux of its model substrate calcein decreased to ~55 % of the initial efflux rate under folate-rich conditions. In 2008wt cells, only a small decrease in efflux was observed. Folate depletion for 5–10 days markedly increased (~500 %) cellular steady-state accumulation of calcein in 2008/MRP1 cells and moderately in 2008wt cells. A subsequent short (24 h) exposure to 2.3 μM
l
-leucovorin decreased calcein levels again in MRP1-overexpressing cells. Folate deprivation markedly increased growth inhibitory effects of the established MRP1 substrates daunorubicin (~twofold), doxorubicin (~fivefold), and methotrexate (~83-fold) in MRP1-overexpressing cells, proportional to MRP1 expression. In conclusion, this study demonstrates that increased cellular folate concentrations induce MRP1/ABCC1-related drug efflux and drug resistance. These results have important implications in the understanding of the role of MRP1 and its homologs in clinical drug resistance.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>24595806</pmid><doi>10.1007/s00280-014-2421-0</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antineoplastic agents Biological and medical sciences Biological Transport Cancer Research Cell Line, Tumor Drug Resistance - drug effects Folic Acid - metabolism Humans Medical sciences Medicine Medicine & Public Health Methotrexate - pharmacology Multidrug Resistance-Associated Proteins - drug effects Multidrug Resistance-Associated Proteins - metabolism Oncology Original Article Pharmacology. Drug treatments Pharmacology/Toxicology |
| title | Folates provoke cellular efflux and drug resistance of substrates of the multidrug resistance protein 1 (MRP1) |
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