Direct binding of chloroquine to the multidrug resistance protein (MRP)
Identifieur interne : 000738 ( Istex/Corpus ); précédent : 000737; suivant : 000739Direct binding of chloroquine to the multidrug resistance protein (MRP)
Auteurs : Marko Vezmar ; Elias GeorgesSource :
- Biochemical Pharmacology [ 0006-2952 ] ; 1998.
English descriptors
- KwdEn :
- Teeft :
- Acad, Azide, Biochem, Biochem biophys, Biochem pharmacol, Biol, Biol chem, Borst, Cell lines, Cells transfected, Chem, Chloroquine, Chloroquine accumulation, Chloroquine efflux, Chloroquine resistance, Chloroquine transport, Cole, Deeley, Direct binding, Drug accumulation, Drug binding, Drug efflux, Drug transport, Drug transport studies, Efflux, Falciparum, Glutathione, Iaaq, Intact cells, Leukotriene, Ltc4, Monoclonal antibody, Multidrug, Multidrug resistance, Multidrug resistance protein, Natl, Other drugs, Overexpression, Parental, Parental cells, Pfmdr1, Pfmdr1 gene, Pharmacol, Photoaffinity, Plasma membranes, Plasmodium, Plasmodium falciparum, Proc, Proc natl acad, Resistant cells, Sclc cells, Sodium azide, Transporter, Tumor cell lines, Unmodified drugs, Vezmar, Vinblastine.
Abstract
Abstract: Multidrug resistance protein (MRP) transports a range of compounds that include glutathione S-conjugates, amphiphilic anionic drugs, and natural-product toxins. However, the mechanism of MRP drug binding and transport is presently unclear. We recently demonstrated the direct binding of a quinoline-based photoactive drug, N-{4-[1-hydroxy-2-(dibutylamino)ethyl] quinolin-8-yl}-4-azidosalicylamide (IAAQ), to MRP at a biologically relevant site [Vezmar et al., Biochem Biophys Res Commun 241: 104–111, 1997]. In the present report, we demonstrated that the lysosomotropic or antimalarial drug chloroquine is a substrate for MRP. Specifically, our results showed that chloroquine, similar to leukotriene C4 (LTC4) and 3-(3-(2-(7-chloro-2-quinolinyl)ethenyl-phenyl)((3-(dimethyl amino-3-oxo propyl)thio)methyl)thio) propanoic acid (MK 571), inhibits the photoaffinity labeling of MRP by IAAQ. Furthermore, cell growth assays showed MRP-expressing multidrug-resistant cells (H69/AR and HL60/AR) to be more resistant to chloroquine than their parental cells (i.e., ic50 of 121 μM versus 28 μM chloroquine for H69/AR and H69, respectively). Moreover, MK 571, an LTD4 receptor antagonist, reversed the resistance of H69/AR cells to chloroquine. Drug transport studies using [14C]chloroquine demonstrated that MRP-expressing cells accumulate less drug than the parental drug-sensitive cells. The reduced accumulation of [14C]chloroquine in resistant cells was ATP dependent and was due to enhanced drug efflux. Taken together, the results of this study show that MRP modulates the transport of chloroquine by direct binding.
Url:
DOI: 10.1016/S0006-2952(98)00217-2
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Direct binding of chloroquine to the multidrug resistance protein (MRP)</title><author><name sortKey="Vezmar, Marko" sort="Vezmar, Marko" uniqKey="Vezmar M" first="Marko" last="Vezmar">Marko Vezmar</name><affiliation><mods:affiliation>Institute of Parasitology, McGill University, Ste-Anne de Bellevue, Quebec, Canada</mods:affiliation></affiliation></author><author><name sortKey="Georges, Elias" sort="Georges, Elias" uniqKey="Georges E" first="Elias" last="Georges">Elias Georges</name><affiliation><mods:affiliation>E-mail: Elias_Georges@maclan.McGill.CA</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute of Parasitology, McGill University, Ste-Anne de Bellevue, Quebec, Canada</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:6B16006E9D5C847FCDD595993F404D3E00BAA2EF</idno><date when="1998" year="1998">1998</date><idno type="doi">10.1016/S0006-2952(98)00217-2</idno><idno type="url">https://api.istex.fr/ark:/67375/6H6-6MLBGRH7-S/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">000738</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000738</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Direct binding of chloroquine to the multidrug resistance protein (MRP)</title><author><name sortKey="Vezmar, Marko" sort="Vezmar, Marko" uniqKey="Vezmar M" first="Marko" last="Vezmar">Marko Vezmar</name><affiliation><mods:affiliation>Institute of Parasitology, McGill University, Ste-Anne de Bellevue, Quebec, Canada</mods:affiliation></affiliation></author><author><name sortKey="Georges, Elias" sort="Georges, Elias" uniqKey="Georges E" first="Elias" last="Georges">Elias Georges</name><affiliation><mods:affiliation>E-mail: Elias_Georges@maclan.McGill.CA</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute of Parasitology, McGill University, Ste-Anne de Bellevue, Quebec, Canada</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Biochemical Pharmacology</title><title level="j" type="abbrev">BCP</title><idno type="ISSN">0006-2952</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1998">1998</date><biblScope unit="volume">56</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="733">733</biblScope><biblScope unit="page" to="742">742</biblScope></imprint><idno type="ISSN">0006-2952</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-2952</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>chloroquine</term><term>drug transport</term><term>multidrug resistance</term><term>multidrug resistance protein (MRP)</term><term>photoaffinity labeling</term></keywords><keywords scheme="Teeft" xml:lang="en"><term>Acad</term><term>Azide</term><term>Biochem</term><term>Biochem biophys</term><term>Biochem pharmacol</term><term>Biol</term><term>Biol chem</term><term>Borst</term><term>Cell lines</term><term>Cells transfected</term><term>Chem</term><term>Chloroquine</term><term>Chloroquine accumulation</term><term>Chloroquine efflux</term><term>Chloroquine resistance</term><term>Chloroquine transport</term><term>Cole</term><term>Deeley</term><term>Direct binding</term><term>Drug accumulation</term><term>Drug binding</term><term>Drug efflux</term><term>Drug transport</term><term>Drug transport studies</term><term>Efflux</term><term>Falciparum</term><term>Glutathione</term><term>Iaaq</term><term>Intact cells</term><term>Leukotriene</term><term>Ltc4</term><term>Monoclonal antibody</term><term>Multidrug</term><term>Multidrug resistance</term><term>Multidrug resistance protein</term><term>Natl</term><term>Other drugs</term><term>Overexpression</term><term>Parental</term><term>Parental cells</term><term>Pfmdr1</term><term>Pfmdr1 gene</term><term>Pharmacol</term><term>Photoaffinity</term><term>Plasma membranes</term><term>Plasmodium</term><term>Plasmodium falciparum</term><term>Proc</term><term>Proc natl acad</term><term>Resistant cells</term><term>Sclc cells</term><term>Sodium azide</term><term>Transporter</term><term>Tumor cell lines</term><term>Unmodified drugs</term><term>Vezmar</term><term>Vinblastine</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: Multidrug resistance protein (MRP) transports a range of compounds that include glutathione S-conjugates, amphiphilic anionic drugs, and natural-product toxins. However, the mechanism of MRP drug binding and transport is presently unclear. We recently demonstrated the direct binding of a quinoline-based photoactive drug, N-{4-[1-hydroxy-2-(dibutylamino)ethyl] quinolin-8-yl}-4-azidosalicylamide (IAAQ), to MRP at a biologically relevant site [Vezmar et al., Biochem Biophys Res Commun 241: 104–111, 1997]. In the present report, we demonstrated that the lysosomotropic or antimalarial drug chloroquine is a substrate for MRP. Specifically, our results showed that chloroquine, similar to leukotriene C4 (LTC4) and 3-(3-(2-(7-chloro-2-quinolinyl)ethenyl-phenyl)((3-(dimethyl amino-3-oxo propyl)thio)methyl)thio) propanoic acid (MK 571), inhibits the photoaffinity labeling of MRP by IAAQ. Furthermore, cell growth assays showed MRP-expressing multidrug-resistant cells (H69/AR and HL60/AR) to be more resistant to chloroquine than their parental cells (i.e., ic50 of 121 μM versus 28 μM chloroquine for H69/AR and H69, respectively). Moreover, MK 571, an LTD4 receptor antagonist, reversed the resistance of H69/AR cells to chloroquine. Drug transport studies using [14C]chloroquine demonstrated that MRP-expressing cells accumulate less drug than the parental drug-sensitive cells. The reduced accumulation of [14C]chloroquine in resistant cells was ATP dependent and was due to enhanced drug efflux. Taken together, the results of this study show that MRP modulates the transport of chloroquine by direct binding.</div></front></TEI><istex><corpusName>elsevier</corpusName><keywords><teeft><json:string>chloroquine</json:string><json:string>multidrug</json:string><json:string>efflux</json:string><json:string>iaaq</json:string><json:string>photoaffinity</json:string><json:string>multidrug resistance</json:string><json:string>ltc4</json:string><json:string>biol</json:string><json:string>falciparum</json:string><json:string>biochem</json:string><json:string>multidrug resistance protein</json:string><json:string>pharmacol</json:string><json:string>deeley</json:string><json:string>plasmodium</json:string><json:string>natl</json:string><json:string>direct binding</json:string><json:string>plasmodium falciparum</json:string><json:string>proc natl acad</json:string><json:string>vezmar</json:string><json:string>acad</json:string><json:string>chem</json:string><json:string>vinblastine</json:string><json:string>pfmdr1</json:string><json:string>proc</json:string><json:string>biol chem</json:string><json:string>azide</json:string><json:string>glutathione</json:string><json:string>chloroquine resistance</json:string><json:string>overexpression</json:string><json:string>plasma membranes</json:string><json:string>sodium azide</json:string><json:string>borst</json:string><json:string>cell lines</json:string><json:string>intact cells</json:string><json:string>transporter</json:string><json:string>leukotriene</json:string><json:string>tumor cell lines</json:string><json:string>drug efflux</json:string><json:string>resistant cells</json:string><json:string>parental cells</json:string><json:string>drug accumulation</json:string><json:string>biochem pharmacol</json:string><json:string>cole</json:string><json:string>biochem biophys</json:string><json:string>drug binding</json:string><json:string>cells transfected</json:string><json:string>drug transport</json:string><json:string>pfmdr1 gene</json:string><json:string>monoclonal antibody</json:string><json:string>chloroquine transport</json:string><json:string>chloroquine accumulation</json:string><json:string>chloroquine efflux</json:string><json:string>drug transport studies</json:string><json:string>other drugs</json:string><json:string>unmodified drugs</json:string><json:string>sclc cells</json:string><json:string>parental</json:string></teeft></keywords><author><json:item><name>Marko Vezmar</name><affiliations><json:string>Institute of Parasitology, McGill University, Ste-Anne de Bellevue, Quebec, Canada</json:string></affiliations></json:item><json:item><name>Elias Georges</name><affiliations><json:string>E-mail: Elias_Georges@maclan.McGill.CA</json:string><json:string>Institute of Parasitology, McGill University, Ste-Anne de Bellevue, Quebec, Canada</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Chemotherapy and Metabolic Inhibitors</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>multidrug resistance</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>chloroquine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>multidrug resistance protein (MRP)</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>drug transport</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>photoaffinity labeling</value></json:item></subject><articleId><json:string>5778</json:string></articleId><arkIstex>ark:/67375/6H6-6MLBGRH7-S</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>Full-length article</json:string></originalGenre><abstract>Abstract: Multidrug resistance protein (MRP) transports a range of compounds that include glutathione S-conjugates, amphiphilic anionic drugs, and natural-product toxins. However, the mechanism of MRP drug binding and transport is presently unclear. We recently demonstrated the direct binding of a quinoline-based photoactive drug, N-{4-[1-hydroxy-2-(dibutylamino)ethyl] quinolin-8-yl}-4-azidosalicylamide (IAAQ), to MRP at a biologically relevant site [Vezmar et al., Biochem Biophys Res Commun 241: 104–111, 1997]. In the present report, we demonstrated that the lysosomotropic or antimalarial drug chloroquine is a substrate for MRP. Specifically, our results showed that chloroquine, similar to leukotriene C4 (LTC4) and 3-(3-(2-(7-chloro-2-quinolinyl)ethenyl-phenyl)((3-(dimethyl amino-3-oxo propyl)thio)methyl)thio) propanoic acid (MK 571), inhibits the photoaffinity labeling of MRP by IAAQ. Furthermore, cell growth assays showed MRP-expressing multidrug-resistant cells (H69/AR and HL60/AR) to be more resistant to chloroquine than their parental cells (i.e., ic50 of 121 μM versus 28 μM chloroquine for H69/AR and H69, respectively). Moreover, MK 571, an LTD4 receptor antagonist, reversed the resistance of H69/AR cells to chloroquine. Drug transport studies using [14C]chloroquine demonstrated that MRP-expressing cells accumulate less drug than the parental drug-sensitive cells. The reduced accumulation of [14C]chloroquine in resistant cells was ATP dependent and was due to enhanced drug efflux. Taken together, the results of this study show that MRP modulates the transport of chloroquine by direct binding.</abstract><qualityIndicators><refBibsNative>true</refBibsNative><abstractWordCount>211</abstractWordCount><abstractCharCount>1626</abstractCharCount><keywordCount>6</keywordCount><score>9.532</score><pdfWordCount>5834</pdfWordCount><pdfCharCount>35748</pdfCharCount><pdfVersion>1.2</pdfVersion><pdfPageCount>10</pdfPageCount><pdfPageSize>596 x 792 pts</pdfPageSize></qualityIndicators><title>Direct binding of chloroquine to the multidrug resistance protein (MRP)</title><pmid><json:string>9751078</json:string></pmid><pii><json:string>S0006-2952(98)00217-2</json:string></pii><genre><json:string>research-article</json:string></genre><host><title>Biochemical Pharmacology</title><language><json:string>unknown</json:string></language><publicationDate>1998</publicationDate><issn><json:string>0006-2952</json:string></issn><pii><json:string>S0006-2952(00)X0085-8</json:string></pii><volume>56</volume><issue>6</issue><pages><first>733</first><last>742</last></pages><genre><json:string>journal</json:string></genre></host><namedEntities><unitex><date><json:string>1998</json:string></date><geogName></geogName><orgName><json:string>Engineering Research Council of Canada</json:string><json:string>Elsevier Science Inc</json:string><json:string>Cayman Chemical Co.</json:string><json:string>NSERC</json:string><json:string>Amersham Biochemical Inc.</json:string><json:string>BIOCHEM</json:string><json:string>Amersham Inc.</json:string><json:string>Cancer Research Laboratories</json:string><json:string>CANADA ABSTRACT</json:string><json:string>Institute of Parasitology</json:string><json:string>INSTITUTE OF PARASITOLOGY, MCGILL UNIVERSITY, STE</json:string><json:string>Kansas State University</json:string><json:string>National Cancer Institute of Canada</json:string><json:string>NCIC</json:string></orgName><orgName_funder><json:string>National Cancer Institute of Canada</json:string><json:string>NCIC</json:string></orgName_funder><orgName_provider></orgName_provider><persName><json:string>E.G. Research</json:string><json:string>Elias Georges</json:string><json:string>P. C. Cole</json:string><json:string>S. P. Cole</json:string><json:string>A. W. Ford</json:string><json:string>E. Georges</json:string><json:string>M. Vezmar</json:string><json:string>M. Center</json:string><json:string>Susan</json:string><json:string>In</json:string><json:string>The</json:string><json:string>Leann Tilley</json:string><json:string>Leslie W. Deady</json:string><json:string>Anne de Bellevue</json:string></persName><placeName><json:string>Cytotoxicity</json:string><json:string>Canada</json:string><json:string>Quebec</json:string><json:string>Fairbanks</json:string></placeName><ref_url></ref_url><ref_bibl><json:string>[50]</json:string><json:string>Cole et al. [31]</json:string><json:string>[60, 61]</json:string><json:string>Rappa et al. [23]</json:string><json:string>[67, 68]</json:string><json:string>[26, 28]</json:string><json:string>[11]</json:string><json:string>[21, 22]</json:string><json:string>[16, 20, 21, 28, 45, 52]</json:string><json:string>Vezmar et al.</json:string><json:string>Towbin et al. [44]</json:string><json:string>[70]</json:string><json:string>[67, 68, 70]</json:string><json:string>[54]</json:string><json:string>[16]</json:string><json:string>Cole et al. [10]</json:string><json:string>[53]</json:string><json:string>[8, 9]</json:string><json:string>[28, 48, 49]</json:string><json:string>Lowry et al. [41]</json:string><json:string>[63]</json:string><json:string>[69]</json:string><json:string>[62]</json:string><json:string>Lin et al. [40]</json:string><json:string>[24]</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/6H6-6MLBGRH7-S</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - pharmacology & pharmacy</json:string></wos><scienceMetrix><json:string>1 - health sciences</json:string><json:string>2 - clinical medicine</json:string><json:string>3 - pharmacology & pharmacy</json:string></scienceMetrix><scopus><json:string>1 - Life Sciences</json:string><json:string>2 - Pharmacology, Toxicology and Pharmaceutics</json:string><json:string>3 - Pharmacology</json:string><json:string>1 - Life Sciences</json:string><json:string>2 - Biochemistry, Genetics and Molecular Biology</json:string><json:string>3 - Biochemistry</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences medicales</json:string><json:string>4 - pneumologie</json:string></inist></categories><publicationDate>1998</publicationDate><copyrightDate>1998</copyrightDate><doi><json:string>10.1016/S0006-2952(98)00217-2</json:string></doi><id>6B16006E9D5C847FCDD595993F404D3E00BAA2EF</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-6MLBGRH7-S/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-6MLBGRH7-S/bundle.zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/6H6-6MLBGRH7-S/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Direct binding of chloroquine to the multidrug resistance protein (MRP)</title><title level="a" type="sub" xml:lang="en">Possible role for MRP in chloroquine drug transport and resistance in tumor cells</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher scheme="https://scientific-publisher.data.istex.fr">ELSEVIER</publisher><availability><licence><p>©1998 Elsevier Science Inc.</p></licence><p scheme="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-HKKZVM7B-M">elsevier</p></availability><date>1998</date></publicationStmt><notesStmt><note type="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note><note type="content">Section title: Original Articles</note><note type="content">FIG. 1: Organic structures of quinoline-based drugs: MK 571, chloroquine, and IAAQ (N-{4-[1-hydroxy-2-(dibutylamino)ethyl] quinolin-8-yl}-4-azidosalicylamide).</note><note type="content">FIG. 2: Effects of chloroquine, vinblastine, MK 571, and LTC4 on photoaffinity labeling of MRP in intact cells (A) and in plasma membranes (B). H69 or H69/AR cells were photoaffinity labeled with 0.25 μM IAAQ in the absence (lanes 2A and 1A, respectively) or presence of 300- and 1000-fold molar excess of vinblastine (VLB), chloroquine (CQ), or 25- to 75-fold of LTC4 or 75- to 1000-fold MK 571 (lanes 3A–12A, respectively). Similarly, plasma membranes from H69 and H69/AR cells were photoaffinity labeled with 0.25 μM IAAQ in the absence (lanes 2B and 1B, respectively) and the presence of 300- to 1000-fold molar excess of vinblastine (VLB), chloroquine (CQ), or MK 571 (lanes 3B–8B, respectively). The numbers on the left of each panel are Mr standards in kilodaltons.</note><note type="content">FIG. 3: Chloroquine cross-resistance and reversal with MK 571 in tumor cell lines. Drug-sensitive (H69 or HL60) and -resistant (H69/AR or HL60/AR) cells were plated at 0.5 to 1.0 × 104 and incubated in increasing concentrations of chloroquine (1–500 μM) (Fig. 3A, a and b, respectively). The effects of 10 and 30 μM MK 571 on the chloroquine cross-resistance of H69 and H69/AR are shown in Fig. 3B, a and b, respectively. The ic50 values were determined from the graph. Each value is the mean ± SD of three experiments in which triplicates were assayed. Figure 3C shows a Western blot of total cell lysates from MRP-overexpressing cells (H69/AR and HL60/AR) and their parental cells (H69 and HL60) probed with QCRL-1 monoclonal antibody.</note><note type="content">FIG. 4: [14C]Chloroquine accumulation in MRP-expressing cells and their parental cells. Drug sensitive (H69 or HL60) and -resistant (H69/AR and HL60/AR) cells were incubated in the presence of 1 μM [14C]chloroquine at 37°. Samples were removed, and the associated radioactivity was determined at 5–60 min by fluorography (Fig. 4, A and C). Similarly, cells were incubated in the presence of 1 μM [14C]chloroquine in the absence and in the presence of 100 nM sodium azide and 10 mM 2-deoxy-glucose (Fig. 4, B and D). Each value is the mean ± SD of three experiments in which triplicates were assayed.</note><note type="content">FIG. 5: [14C]Chloroquine efflux from MRP-overexpressing cells and their parental cells. Drug-sensitive (H69 or HL60) and -resistant (H69/AR or HL60/AR) cells were loaded with 10 μM [14C]chloroquine in the absence or presence of 10 mM sodium azide for 30 min after which drug extrusion was potentiated with the administration of 5 mM d-glucose to one half of the samples. For the remaining half of the samples, [14C]chloroquine levels were determined in the presence of sodium azide. Samples were collected, and the amount of drug remaining in the cells was measured by fluorography. Each value is the mean ± SD of two experiments in which triplicates were assayed.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Direct binding of chloroquine to the multidrug resistance protein (MRP)</title><title level="a" type="sub" xml:lang="en">Possible role for MRP in chloroquine drug transport and resistance in tumor cells</title><author xml:id="author-0000"><persName><forename type="first">Marko</forename><surname>Vezmar</surname></persName><affiliation>Institute of Parasitology, McGill University, Ste-Anne de Bellevue, Quebec, Canada</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Elias</forename><surname>Georges</surname></persName><email>Elias_Georges@maclan.McGill.CA</email><note type="correspondence"><p>Corresponding author: Elias Georges, Ph.D., Institute of Parasitology, McGill University, 21,111 Lakeshore Road, Ste-Anne de Bellevue, Quebec, Canada H9X 3V9. Tel. (514) 398-8137; FAX (514) 398-7857</p></note><affiliation>Institute of Parasitology, McGill University, Ste-Anne de Bellevue, Quebec, Canada</affiliation></author><idno type="istex">6B16006E9D5C847FCDD595993F404D3E00BAA2EF</idno><idno type="ark">ark:/67375/6H6-6MLBGRH7-S</idno><idno type="DOI">10.1016/S0006-2952(98)00217-2</idno><idno type="PII">S0006-2952(98)00217-2</idno><idno type="article-id">5778</idno></analytic><monogr><title level="j">Biochemical Pharmacology</title><title level="j" type="abbrev">BCP</title><idno type="pISSN">0006-2952</idno><idno type="PII">S0006-2952(00)X0085-8</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1998"></date><biblScope unit="volume">56</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="733">733</biblScope><biblScope unit="page" to="742">742</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1998</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Abstract: Multidrug resistance protein (MRP) transports a range of compounds that include glutathione S-conjugates, amphiphilic anionic drugs, and natural-product toxins. However, the mechanism of MRP drug binding and transport is presently unclear. We recently demonstrated the direct binding of a quinoline-based photoactive drug, N-{4-[1-hydroxy-2-(dibutylamino)ethyl] quinolin-8-yl}-4-azidosalicylamide (IAAQ), to MRP at a biologically relevant site [Vezmar et al., Biochem Biophys Res Commun 241: 104–111, 1997]. In the present report, we demonstrated that the lysosomotropic or antimalarial drug chloroquine is a substrate for MRP. Specifically, our results showed that chloroquine, similar to leukotriene C4 (LTC4) and 3-(3-(2-(7-chloro-2-quinolinyl)ethenyl-phenyl)((3-(dimethyl amino-3-oxo propyl)thio)methyl)thio) propanoic acid (MK 571), inhibits the photoaffinity labeling of MRP by IAAQ. Furthermore, cell growth assays showed MRP-expressing multidrug-resistant cells (H69/AR and HL60/AR) to be more resistant to chloroquine than their parental cells (i.e., ic50 of 121 μM versus 28 μM chloroquine for H69/AR and H69, respectively). Moreover, MK 571, an LTD4 receptor antagonist, reversed the resistance of H69/AR cells to chloroquine. Drug transport studies using [14C]chloroquine demonstrated that MRP-expressing cells accumulate less drug than the parental drug-sensitive cells. The reduced accumulation of [14C]chloroquine in resistant cells was ATP dependent and was due to enhanced drug efflux. Taken together, the results of this study show that MRP modulates the transport of chloroquine by direct binding.</p></abstract><textClass><keywords scheme="keyword"><list><head>article-category</head><item><term>Chemotherapy and Metabolic Inhibitors</term></item></list></keywords></textClass><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>multidrug resistance</term></item><item><term>chloroquine</term></item><item><term>multidrug resistance protein (MRP)</term></item><item><term>drug transport</term></item><item><term>photoaffinity labeling</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1998">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-6MLBGRH7-S/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier, elements deleted: ce:floats; body; tail"><istex:xmlDeclaration>version="1.0" encoding="UTF-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 4.5.2//EN//XML" URI="art452.dtd" name="istex:docType"><istex:entity SYSTEM="gr1" NDATA="IMAGE" name="GR1"></istex:entity><istex:entity SYSTEM="gr2" NDATA="IMAGE" name="GR2"></istex:entity><istex:entity SYSTEM="gr3" NDATA="IMAGE" name="GR3"></istex:entity><istex:entity SYSTEM="gr4" NDATA="IMAGE" name="GR4"></istex:entity><istex:entity SYSTEM="gr5" NDATA="IMAGE" name="GR5"></istex:entity></istex:docType><istex:document><converted-article version="4.5.2" docsubtype="fla" xml:lang="en"><item-info><jid>BCP</jid><aid>5778</aid><ce:pii>S0006-2952(98)00217-2</ce:pii><ce:doi>10.1016/S0006-2952(98)00217-2</ce:doi><ce:copyright type="full-transfer" year="1998">Elsevier Science Inc.</ce:copyright><ce:doctopics><ce:doctopic><ce:text>Chemotherapy and Metabolic Inhibitors</ce:text></ce:doctopic></ce:doctopics></item-info><head><ce:dochead><ce:textfn>Original Articles</ce:textfn></ce:dochead><ce:title>Direct binding of chloroquine to the multidrug resistance protein (MRP)</ce:title><ce:subtitle>Possible role for MRP in chloroquine drug transport and resistance in tumor cells</ce:subtitle><ce:author-group><ce:author><ce:given-name>Marko</ce:given-name><ce:surname>Vezmar</ce:surname><ce:cross-ref refid="AFF1"><ce:sup loc="post">a</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Elias</ce:given-name><ce:surname>Georges</ce:surname><ce:cross-ref refid="AFF1"><ce:sup loc="post">a</ce:sup></ce:cross-ref><ce:cross-ref refid="CORR1">*</ce:cross-ref><ce:e-address type="email">Elias_Georges@maclan.McGill.CA</ce:e-address></ce:author><ce:affiliation id="AFF1"><ce:label>a</ce:label><ce:textfn>Institute of Parasitology, McGill University, Ste-Anne de Bellevue, Quebec, Canada</ce:textfn></ce:affiliation><ce:correspondence id="CORR1"><ce:label>*</ce:label><ce:text>Corresponding author: Elias Georges, Ph.D., Institute of Parasitology, McGill University, 21,111 Lakeshore Road, Ste-Anne de Bellevue, Quebec, Canada H9X 3V9. Tel. (514) 398-8137; FAX (514) 398-7857</ce:text></ce:correspondence></ce:author-group><ce:date-received day="25" month="2" year="1998"></ce:date-received><ce:date-accepted day="27" month="5" year="1998"></ce:date-accepted><ce:abstract class="author"><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para view="all" id="simple-para.0035">Multidrug resistance protein (MRP) transports a range of compounds that include glutathione <ce:italic>S</ce:italic>-conjugates, amphiphilic anionic drugs, and natural-product toxins. However, the mechanism of MRP drug binding and transport is presently unclear. We recently demonstrated the direct binding of a quinoline-based photoactive drug, <ce:italic>N</ce:italic>-{4-[1-hydroxy-2-(dibutylamino)ethyl] quinolin-8-yl}-4-azidosalicylamide (IAAQ), to MRP at a biologically relevant site [Vezmar <ce:italic>et al</ce:italic>., <ce:italic>Biochem Biophys Res Commun</ce:italic> 241: 104–111, 1997]. In the present report, we demonstrated that the lysosomotropic or antimalarial drug chloroquine is a substrate for MRP. Specifically, our results showed that chloroquine, similar to leukotriene C<ce:inf loc="post">4</ce:inf> (LTC<ce:inf loc="post">4</ce:inf>) and 3-(3-(2-(7-chloro-2-quinolinyl)ethenyl-phenyl)((3-(dimethyl amino-3-oxo propyl)thio)methyl)thio) propanoic acid (MK 571), inhibits the photoaffinity labeling of MRP by IAAQ. Furthermore, cell growth assays showed MRP-expressing multidrug-resistant cells (H69/AR and HL60/AR) to be more resistant to chloroquine than their parental cells (i.e., <ce:small-caps>ic</ce:small-caps><ce:inf loc="post">50</ce:inf> of 121 μM versus 28 μM chloroquine for H69/AR and H69, respectively). Moreover, MK 571, an LTD<ce:inf loc="post">4</ce:inf> receptor antagonist, reversed the resistance of H69/AR cells to chloroquine. Drug transport studies using [<ce:sup loc="post">14</ce:sup>C]chloroquine demonstrated that MRP-expressing cells accumulate less drug than the parental drug-sensitive cells. The reduced accumulation of [<ce:sup loc="post">14</ce:sup>C]chloroquine in resistant cells was ATP dependent and was due to enhanced drug efflux. Taken together, the results of this study show that MRP modulates the transport of chloroquine by direct binding.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords class="keyword"><ce:section-title>Keywords</ce:section-title><ce:keyword><ce:text>multidrug resistance</ce:text></ce:keyword><ce:keyword><ce:text>chloroquine</ce:text></ce:keyword><ce:keyword><ce:text>multidrug resistance protein (MRP)</ce:text></ce:keyword><ce:keyword><ce:text>drug transport</ce:text></ce:keyword><ce:keyword><ce:text>photoaffinity labeling</ce:text></ce:keyword></ce:keywords></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Direct binding of chloroquine to the multidrug resistance protein (MRP)</title><subTitle>Possible role for MRP in chloroquine drug transport and resistance in tumor cells</subTitle></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Direct binding of chloroquine to the multidrug resistance protein (MRP)</title><subTitle>Possible role for MRP in chloroquine drug transport and resistance in tumor cells</subTitle></titleInfo><name type="personal"><namePart type="given">Marko</namePart><namePart type="family">Vezmar</namePart><affiliation>Institute of Parasitology, McGill University, Ste-Anne de Bellevue, Quebec, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Elias</namePart><namePart type="family">Georges</namePart><affiliation>E-mail: Elias_Georges@maclan.McGill.CA</affiliation><affiliation>Institute of Parasitology, McGill University, Ste-Anne de Bellevue, Quebec, Canada</affiliation><description>Corresponding author: Elias Georges, Ph.D., Institute of Parasitology, McGill University, 21,111 Lakeshore Road, Ste-Anne de Bellevue, Quebec, Canada H9X 3V9. Tel. (514) 398-8137; FAX (514) 398-7857</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Full-length article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1998</dateIssued><copyrightDate encoding="w3cdtf">1998</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><abstract lang="en">Abstract: Multidrug resistance protein (MRP) transports a range of compounds that include glutathione S-conjugates, amphiphilic anionic drugs, and natural-product toxins. However, the mechanism of MRP drug binding and transport is presently unclear. We recently demonstrated the direct binding of a quinoline-based photoactive drug, N-{4-[1-hydroxy-2-(dibutylamino)ethyl] quinolin-8-yl}-4-azidosalicylamide (IAAQ), to MRP at a biologically relevant site [Vezmar et al., Biochem Biophys Res Commun 241: 104–111, 1997]. In the present report, we demonstrated that the lysosomotropic or antimalarial drug chloroquine is a substrate for MRP. Specifically, our results showed that chloroquine, similar to leukotriene C4 (LTC4) and 3-(3-(2-(7-chloro-2-quinolinyl)ethenyl-phenyl)((3-(dimethyl amino-3-oxo propyl)thio)methyl)thio) propanoic acid (MK 571), inhibits the photoaffinity labeling of MRP by IAAQ. Furthermore, cell growth assays showed MRP-expressing multidrug-resistant cells (H69/AR and HL60/AR) to be more resistant to chloroquine than their parental cells (i.e., ic50 of 121 μM versus 28 μM chloroquine for H69/AR and H69, respectively). Moreover, MK 571, an LTD4 receptor antagonist, reversed the resistance of H69/AR cells to chloroquine. Drug transport studies using [14C]chloroquine demonstrated that MRP-expressing cells accumulate less drug than the parental drug-sensitive cells. The reduced accumulation of [14C]chloroquine in resistant cells was ATP dependent and was due to enhanced drug efflux. Taken together, the results of this study show that MRP modulates the transport of chloroquine by direct binding.</abstract><note type="content">Section title: Original Articles</note><note type="content">FIG. 1: Organic structures of quinoline-based drugs: MK 571, chloroquine, and IAAQ (N-{4-[1-hydroxy-2-(dibutylamino)ethyl] quinolin-8-yl}-4-azidosalicylamide).</note><note type="content">FIG. 2: Effects of chloroquine, vinblastine, MK 571, and LTC4 on photoaffinity labeling of MRP in intact cells (A) and in plasma membranes (B). H69 or H69/AR cells were photoaffinity labeled with 0.25 μM IAAQ in the absence (lanes 2A and 1A, respectively) or presence of 300- and 1000-fold molar excess of vinblastine (VLB), chloroquine (CQ), or 25- to 75-fold of LTC4 or 75- to 1000-fold MK 571 (lanes 3A–12A, respectively). Similarly, plasma membranes from H69 and H69/AR cells were photoaffinity labeled with 0.25 μM IAAQ in the absence (lanes 2B and 1B, respectively) and the presence of 300- to 1000-fold molar excess of vinblastine (VLB), chloroquine (CQ), or MK 571 (lanes 3B–8B, respectively). The numbers on the left of each panel are Mr standards in kilodaltons.</note><note type="content">FIG. 3: Chloroquine cross-resistance and reversal with MK 571 in tumor cell lines. Drug-sensitive (H69 or HL60) and -resistant (H69/AR or HL60/AR) cells were plated at 0.5 to 1.0 × 104 and incubated in increasing concentrations of chloroquine (1–500 μM) (Fig. 3A, a and b, respectively). The effects of 10 and 30 μM MK 571 on the chloroquine cross-resistance of H69 and H69/AR are shown in Fig. 3B, a and b, respectively. The ic50 values were determined from the graph. Each value is the mean ± SD of three experiments in which triplicates were assayed. Figure 3C shows a Western blot of total cell lysates from MRP-overexpressing cells (H69/AR and HL60/AR) and their parental cells (H69 and HL60) probed with QCRL-1 monoclonal antibody.</note><note type="content">FIG. 4: [14C]Chloroquine accumulation in MRP-expressing cells and their parental cells. Drug sensitive (H69 or HL60) and -resistant (H69/AR and HL60/AR) cells were incubated in the presence of 1 μM [14C]chloroquine at 37°. Samples were removed, and the associated radioactivity was determined at 5–60 min by fluorography (Fig. 4, A and C). Similarly, cells were incubated in the presence of 1 μM [14C]chloroquine in the absence and in the presence of 100 nM sodium azide and 10 mM 2-deoxy-glucose (Fig. 4, B and D). Each value is the mean ± SD of three experiments in which triplicates were assayed.</note><note type="content">FIG. 5: [14C]Chloroquine efflux from MRP-overexpressing cells and their parental cells. Drug-sensitive (H69 or HL60) and -resistant (H69/AR or HL60/AR) cells were loaded with 10 μM [14C]chloroquine in the absence or presence of 10 mM sodium azide for 30 min after which drug extrusion was potentiated with the administration of 5 mM d-glucose to one half of the samples. For the remaining half of the samples, [14C]chloroquine levels were determined in the presence of sodium azide. Samples were collected, and the amount of drug remaining in the cells was measured by fluorography. Each value is the mean ± SD of two experiments in which triplicates were assayed.</note><subject><genre>article-category</genre><topic>Chemotherapy and Metabolic Inhibitors</topic></subject><subject lang="en"><genre>Keywords</genre><topic>multidrug resistance</topic><topic>chloroquine</topic><topic>multidrug resistance protein (MRP)</topic><topic>drug transport</topic><topic>photoaffinity labeling</topic></subject><relatedItem type="host"><titleInfo><title>Biochemical Pharmacology</title></titleInfo><titleInfo type="abbreviated"><title>BCP</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1998</dateIssued></originInfo><identifier type="ISSN">0006-2952</identifier><identifier type="PII">S0006-2952(00)X0085-8</identifier><part><date>1998</date><detail type="volume"><number>56</number><caption>vol.</caption></detail><detail type="issue"><number>6</number><caption>no.</caption></detail><extent unit="issue-pages"><start>667</start><end>780</end></extent><extent unit="pages"><start>733</start><end>742</end></extent></part></relatedItem><identifier type="istex">6B16006E9D5C847FCDD595993F404D3E00BAA2EF</identifier><identifier type="ark">ark:/67375/6H6-6MLBGRH7-S</identifier><identifier type="DOI">10.1016/S0006-2952(98)00217-2</identifier><identifier type="PII">S0006-2952(98)00217-2</identifier><identifier type="ArticleID">5778</identifier><accessCondition type="use and reproduction" contentType="copyright">©1998 Elsevier Science Inc.</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-HKKZVM7B-M">elsevier</recordContentSource><recordOrigin>Elsevier Science Inc., ©1998</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-6MLBGRH7-S/record.json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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