Identification of two distinct intracellular sites that contribute to the modulation of multidrug resistance in P388/ADR cells expressing P‐glycoprotein
Identifieur interne : 001A25 ( Istex/Corpus ); précédent : 001A24; suivant : 001A26Identification of two distinct intracellular sites that contribute to the modulation of multidrug resistance in P388/ADR cells expressing P‐glycoprotein
Auteurs : Lawrence D. Mayer ; Kye-Taek Lim ; Daria HartleySource :
- Journal of Experimental Therapeutics and Oncology [ 1359-4117 ] ; 2002-03.
Abstract
Although the ability of chemosensitizers to modulate P‐glycoprotein (PGP)‐based multidrug resistance (MDR) has been extensively studied, relatively little is known about the cellular pharmacology of the PGP inhibitors themselves in MDR cells. The studies described here have correlated the in vitro accumulation and retention properties of verapamil (VRP) in murine P388 (sensitive) and P388/ADR (MDR) cells with doxorubicin (DOX) uptake and cytotoxicity modulation characteristics in order to better understand VRP–tumor cell interactions that give rise to MDR modulation. VRP is rapidly taken up by DOX‐sensitive and ‐resistant P388 cells where greater than 50% maximal VRP uptake occurs within 10 min of initial exposure at 37°C. Whereas chemosensitization and DOX uptake in P388/ADR cells increase with increasing VRP concentration until a plateau is achieved at approximately 5 μM VRP, cellular modulator levels increase proportionally with increasing VPR concentrations beyond 20 μM. Subsequent to removal of noncell‐associated modulator, VRP levels in both sensitive and resistant cells rapidly fall below 10% of those obtained at uptake equilibrium. However, a residual amount of VRP remains associated with the cells for extended time periods after the cells are washed. Pulse exposures of P388/ADR cells to high concentrations of VRP (50–100 μM) are capable of providing extended cell‐associated VRP levels comparable to those obtained with continuous exposure at biologically active VRP concentrations (1–3 μM) and this leads to chemosensitization. These results are consistent with the existence of high‐ and low‐affinity intracellular VRP pools in P388 MDR cells, both of which can contribute to the reversal of drug resistance. It is suggested that these properties should be taken into consideration during the design and evaluation of preclinical in vivo MDR models where pulsed exposure to high concentrations of resistance modulators often occurs. Special attention must be given to whether such high concentration pulses are desirable and/or achievable in relevant clinical settings.
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DOI: 10.1046/j.1359-4117.2002.1009x.x
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Mayer</name><affiliation><mods:affiliation>Department of Advanced Therapeutics, The British Columbia Cancer Agency, 600 West 10th Ave. Vancouver, BC V5Z 4E6,</mods:affiliation></affiliation><affiliation><mods:affiliation>Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall Vancouver, BC V6T 1W5,</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence address: L.D. Mayer, Department of Advanced Therapeutics, The British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC, Canada V5Z 4E6.</mods:affiliation></affiliation></author><author><name sortKey="Lim, Kye Aek" sort="Lim, Kye Aek" uniqKey="Lim K" first="Kye-Taek" last="Lim">Kye-Taek Lim</name><affiliation><mods:affiliation>Division of Protein Engineering, Institute of Biotechnology, Chonnam National University, Kwangju City, Yongbong Dong 300, South Korea.</mods:affiliation></affiliation></author><author><name sortKey="Hartley, Daria" sort="Hartley, Daria" uniqKey="Hartley D" first="Daria" last="Hartley">Daria Hartley</name><affiliation><mods:affiliation>Department of Advanced Therapeutics, The British Columbia Cancer Agency, 600 West 10th Ave. Vancouver, BC V5Z 4E6,</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Journal of Experimental Therapeutics and Oncology</title><title level="j" type="alt">JOURNAL OF EXPERIMENTAL THERAPEUTICS AND ONCOLOGY</title><idno type="ISSN">1359-4117</idno><idno type="eISSN">1533-869X</idno><imprint><biblScope unit="vol">2</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="107">107</biblScope><biblScope unit="page" to="120">120</biblScope><biblScope unit="page-count">14</biblScope><publisher>Blackwell Science Inc</publisher><pubPlace>Boston, MA, USA</pubPlace><date type="published" when="2002-03">2002-03</date></imprint><idno type="ISSN">1359-4117</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1359-4117</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Although the ability of chemosensitizers to modulate P‐glycoprotein (PGP)‐based multidrug resistance (MDR) has been extensively studied, relatively little is known about the cellular pharmacology of the PGP inhibitors themselves in MDR cells. The studies described here have correlated the in vitro accumulation and retention properties of verapamil (VRP) in murine P388 (sensitive) and P388/ADR (MDR) cells with doxorubicin (DOX) uptake and cytotoxicity modulation characteristics in order to better understand VRP–tumor cell interactions that give rise to MDR modulation. VRP is rapidly taken up by DOX‐sensitive and ‐resistant P388 cells where greater than 50% maximal VRP uptake occurs within 10 min of initial exposure at 37°C. Whereas chemosensitization and DOX uptake in P388/ADR cells increase with increasing VRP concentration until a plateau is achieved at approximately 5 μM VRP, cellular modulator levels increase proportionally with increasing VPR concentrations beyond 20 μM. Subsequent to removal of noncell‐associated modulator, VRP levels in both sensitive and resistant cells rapidly fall below 10% of those obtained at uptake equilibrium. However, a residual amount of VRP remains associated with the cells for extended time periods after the cells are washed. Pulse exposures of P388/ADR cells to high concentrations of VRP (50–100 μM) are capable of providing extended cell‐associated VRP levels comparable to those obtained with continuous exposure at biologically active VRP concentrations (1–3 μM) and this leads to chemosensitization. These results are consistent with the existence of high‐ and low‐affinity intracellular VRP pools in P388 MDR cells, both of which can contribute to the reversal of drug resistance. It is suggested that these properties should be taken into consideration during the design and evaluation of preclinical in vivo MDR models where pulsed exposure to high concentrations of resistance modulators often occurs. 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<ref target="http://www.tei-c.org/">We use TEI</ref></desc></application></appInfo></encodingDesc><profileDesc><abstract xml:lang="en" style="main"><p>Although the ability of chemosensitizers to modulate P‐glycoprotein (PGP)‐based multidrug resistance (MDR) has been extensively studied, relatively little is known about the cellular pharmacology of the PGP inhibitors themselves in MDR cells. The studies described here have correlated the in vitro accumulation and retention properties of verapamil (VRP) in murine P388 (sensitive) and P388/ADR (MDR) cells with doxorubicin (DOX) uptake and cytotoxicity modulation characteristics in order to better understand VRP–tumor cell interactions that give rise to MDR modulation. VRP is rapidly taken up by DOX‐sensitive and ‐resistant P388 cells where greater than 50% maximal VRP uptake occurs within 10 min of initial exposure at 37°C. Whereas chemosensitization and DOX uptake in P388/ADR cells increase with increasing VRP concentration until a plateau is achieved at approximately 5 μM VRP, cellular modulator levels increase proportionally with increasing VPR concentrations beyond 20 μM. Subsequent to removal of noncell‐associated modulator, VRP levels in both sensitive and resistant cells rapidly fall below 10% of those obtained at uptake equilibrium. However, a residual amount of VRP remains associated with the cells for extended time periods after the cells are washed. Pulse exposures of P388/ADR cells to high concentrations of VRP (50–100 μM) are capable of providing extended cell‐associated VRP levels comparable to those obtained with continuous exposure at biologically active VRP concentrations (1–3 μM) and this leads to chemosensitization. These results are consistent with the existence of high‐ and low‐affinity intracellular VRP pools in P388 MDR cells, both of which can contribute to the reversal of drug resistance. It is suggested that these properties should be taken into consideration during the design and evaluation of preclinical in vivo MDR models where pulsed exposure to high concentrations of resistance modulators often occurs. Special attention must be given to whether such high concentration pulses are desirable and/or achievable in relevant clinical settings.</p></abstract><textClass><keywords xml:lang="en"><term xml:id="k1">Multidrug resistance</term><term xml:id="k2">cancer</term><term xml:id="k3">chemotherapy</term></keywords><keywords rend="tocHeading1"><term>Original Articles</term></keywords></textClass><langUsage><language ident="en"></language></langUsage></profileDesc><revisionDesc><change when="2019-12-20" who="#istex" xml:id="pub2tei">formatting</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/WNG-PJCNFFZ1-X/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Blackwell Science Inc</publisherName><publisherLoc>Boston, MA, USA</publisherLoc></publisherInfo><doi origin="wiley" registered="yes">10.1111/(ISSN)1533-869X</doi><issn type="print">1359-4117</issn><issn type="electronic">1533-869X</issn><idGroup><id type="product" value="JET"></id><id type="publisherDivision" value="ST"></id></idGroup><titleGroup><title type="main" sort="JOURNAL OF EXPERIMENTAL THERAPEUTICS AND ONCOLOGY">Journal of Experimental Therapeutics and Oncology</title><title type="short">Journal of Experimental Therapeutics and Oncology</title></titleGroup></publicationMeta><publicationMeta level="part" position="03002"><doi origin="wiley">10.1111/jet.2002.2.issue-2</doi><numberingGroup><numbering type="journalVolume" number="2">2</numbering><numbering type="journalIssue" number="2">2</numbering></numberingGroup><coverDate startDate="2002-03">March/April 2002</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="0010700" status="forIssue"><doi origin="wiley">10.1046/j.1359-4117.2002.1009x.x</doi><idGroup><id type="unit" value="JET1009"></id></idGroup><countGroup><count type="pageTotal" number="14"></count></countGroup><titleGroup><title type="tocHeading1">Original Articles</title></titleGroup><eventGroup><event type="firstOnline" date="2002-03-08"></event><event type="publishedOnlineFinalForm" date="2002-03-08"></event><event type="xmlConverted" agent="Converter:BPG_TO_WML3G version:2.3.4 mode:FullText source:FullText result:FullText" date="2010-03-29"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-30"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-30"></event></eventGroup><numberingGroup><numbering type="pageFirst" number="107">107</numbering><numbering type="pageLast" number="120">120</numbering></numberingGroup><correspondenceTo>L.D. Mayer, Department of Advanced Therapeutics, The British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC, Canada V5Z 4E6.</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:JET.JET1009.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="0"></count><count type="tableTotal" number="3"></count><count type="referenceTotal" number="40"></count><count type="linksPubMed" number="38"></count><count type="linksCrossRef" number="0"></count></countGroup><titleGroup><title type="main">Identification of two distinct intracellular sites that contribute to the modulation of multidrug resistance in P388/ADR cells expressing P‐glycoprotein</title><title type="shortAuthors">Mayer LD et al.</title><title type="short">Cellular pharmacology of MDR modulation by verapamil</title></titleGroup><creators><creator creatorRole="author" xml:id="cr1" affiliationRef="#a1 #a2" corresponding="yes"><personName><givenNames>Lawrence D.</givenNames><familyName>Mayer</familyName></personName></creator><creator creatorRole="author" xml:id="cr2" affiliationRef="#a3"><personName><givenNames>Kye‐Taek</givenNames><familyName>Lim</familyName></personName></creator><creator creatorRole="author" xml:id="cr3" affiliationRef="#a1"><personName><givenNames>Daria</givenNames><familyName>Hartley</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="a1"><unparsedAffiliation>Department of Advanced Therapeutics, The British Columbia Cancer Agency, 600 West 10th Ave. Vancouver, BC V5Z 4E6,</unparsedAffiliation></affiliation><affiliation xml:id="a2"><unparsedAffiliation>Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall Vancouver, BC V6T 1W5,</unparsedAffiliation></affiliation><affiliation xml:id="a3"><unparsedAffiliation>Division of Protein Engineering, Institute of Biotechnology, Chonnam National University, Kwangju City, Yongbong Dong 300, South Korea.</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en"><keyword xml:id="k1">Multidrug resistance</keyword><keyword xml:id="k2">cancer</keyword><keyword xml:id="k3">chemotherapy</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><p>Although the ability of chemosensitizers to modulate P‐glycoprotein (PGP)‐based multidrug resistance (MDR) has been extensively studied, relatively little is known about the cellular pharmacology of the PGP inhibitors themselves in MDR cells. The studies described here have correlated the in vitro accumulation and retention properties of verapamil (VRP) in murine P388 (sensitive) and P388/ADR (MDR) cells with doxorubicin (DOX) uptake and cytotoxicity modulation characteristics in order to better understand VRP–tumor cell interactions that give rise to MDR modulation. VRP is rapidly taken up by DOX‐sensitive and ‐resistant P388 cells where greater than 50% maximal VRP uptake occurs within 10 min of initial exposure at 37°C. Whereas chemosensitization and DOX uptake in P388/ADR cells increase with increasing VRP concentration until a plateau is achieved at approximately 5 μM VRP, cellular modulator levels increase proportionally with increasing VPR concentrations beyond 20 μM. Subsequent to removal of noncell‐associated modulator, VRP levels in both sensitive and resistant cells rapidly fall below 10% of those obtained at uptake equilibrium. However, a residual amount of VRP remains associated with the cells for extended time periods after the cells are washed. Pulse exposures of P388/ADR cells to high concentrations of VRP (50–100 μM) are capable of providing extended cell‐associated VRP levels comparable to those obtained with continuous exposure at biologically active VRP concentrations (1–3 μM) and this leads to chemosensitization. These results are consistent with the existence of high‐ and low‐affinity intracellular VRP pools in P388 MDR cells, both of which can contribute to the reversal of drug resistance. It is suggested that these properties should be taken into consideration during the design and evaluation of preclinical in vivo MDR models where pulsed exposure to high concentrations of resistance modulators often occurs. Special attention must be given to whether such high concentration pulses are desirable and/or achievable in relevant clinical settings.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Identification of two distinct intracellular sites that contribute to the modulation of multidrug resistance in P388/ADR cells expressing P‐glycoprotein</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Cellular pharmacology of MDR modulation by verapamil</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Identification of two distinct intracellular sites that contribute to the modulation of multidrug resistance in P388/ADR cells expressing P‐glycoprotein</title></titleInfo><name type="personal"><namePart type="given">Lawrence D.</namePart><namePart type="family">Mayer</namePart><affiliation>Department of Advanced Therapeutics, The British Columbia Cancer Agency, 600 West 10th Ave. Vancouver, BC V5Z 4E6,</affiliation><affiliation>Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall Vancouver, BC V6T 1W5,</affiliation><affiliation>Correspondence address: L.D. Mayer, Department of Advanced Therapeutics, The British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC, Canada V5Z 4E6.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kye‐Taek</namePart><namePart type="family">Lim</namePart><affiliation>Division of Protein Engineering, Institute of Biotechnology, Chonnam National University, Kwangju City, Yongbong Dong 300, South Korea.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Daria</namePart><namePart type="family">Hartley</namePart><affiliation>Department of Advanced Therapeutics, The British Columbia Cancer Agency, 600 West 10th Ave. Vancouver, BC V5Z 4E6,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</genre><originInfo><publisher>Blackwell Science Inc</publisher><place><placeTerm type="text">Boston, MA, USA</placeTerm></place><dateIssued encoding="w3cdtf">2002-03</dateIssued><copyrightDate encoding="w3cdtf">2002</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><extent unit="figures">0</extent><extent unit="tables">3</extent><extent unit="references">40</extent><extent unit="linksCrossRef">0</extent></physicalDescription><abstract lang="en">Although the ability of chemosensitizers to modulate P‐glycoprotein (PGP)‐based multidrug resistance (MDR) has been extensively studied, relatively little is known about the cellular pharmacology of the PGP inhibitors themselves in MDR cells. The studies described here have correlated the in vitro accumulation and retention properties of verapamil (VRP) in murine P388 (sensitive) and P388/ADR (MDR) cells with doxorubicin (DOX) uptake and cytotoxicity modulation characteristics in order to better understand VRP–tumor cell interactions that give rise to MDR modulation. VRP is rapidly taken up by DOX‐sensitive and ‐resistant P388 cells where greater than 50% maximal VRP uptake occurs within 10 min of initial exposure at 37°C. Whereas chemosensitization and DOX uptake in P388/ADR cells increase with increasing VRP concentration until a plateau is achieved at approximately 5 μM VRP, cellular modulator levels increase proportionally with increasing VPR concentrations beyond 20 μM. Subsequent to removal of noncell‐associated modulator, VRP levels in both sensitive and resistant cells rapidly fall below 10% of those obtained at uptake equilibrium. However, a residual amount of VRP remains associated with the cells for extended time periods after the cells are washed. Pulse exposures of P388/ADR cells to high concentrations of VRP (50–100 μM) are capable of providing extended cell‐associated VRP levels comparable to those obtained with continuous exposure at biologically active VRP concentrations (1–3 μM) and this leads to chemosensitization. These results are consistent with the existence of high‐ and low‐affinity intracellular VRP pools in P388 MDR cells, both of which can contribute to the reversal of drug resistance. It is suggested that these properties should be taken into consideration during the design and evaluation of preclinical in vivo MDR models where pulsed exposure to high concentrations of resistance modulators often occurs. 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