Modulation by acrolein and chloroacetaldehyde of multidrug resistance mediated by the multidrug resistance-associated protein (MRP)
Acrolein (AC) and chloroacetaldehyde (CHA) are metabolites of the non-multidrug resistance cytotoxic drugs cyclophosphamide and ifosfamide. It has previously been reported that both metabolites can induce extensive depletion of glutathione (GSH) in vitro and in vivo and that this depletion occurs at...
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| Veröffentlicht in: | Clinical cancer research 1996-08, Vol.2 (8), p.1321-1326 |
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| creator | GONZALEZ MANZANO, R WRIGHT, K. A TWENTYMAN, P. R |
| description | Acrolein (AC) and chloroacetaldehyde (CHA) are metabolites of the non-multidrug resistance cytotoxic drugs cyclophosphamide
and ifosfamide. It has previously been reported that both metabolites can induce extensive depletion of glutathione (GSH)
in vitro and in vivo and that this depletion occurs at drug concentrations in the micromolar range. A link between the function
of the multidrug resistance-associated protein (MRP) and the intracellular concentration of GSH has also been demonstrated.
To determine whether AC and CHA can modulate the function of MRP by inducing GSH depletion, we used two human lung cancer
cell lines overexpressing MRP: the large cell carcinoma cell line COR-L23/R and the adenocarcinoma cell line MOR/R0.4, along
with their respective sensitive parental lines, COR-L23/P and MOR/P. We showed that micromolar concentrations of AC and millimolar
concentrations of CHA are able to deplete GSH concentrations in the cell lines studied. In addition, concentrations of 50
micrometer AC and 5 mm CHA could completely reverse the daunorubicin (DNR) and vinblastine accumulation deficit present in
COR-L23/R and partially reverse the DNR accumulation deficit in MOR/R0.4. In contrast, AC and CHA did not reverse the drug
accumulation deficit in the P-glycoprotein-overexpressing lung cancer cell line H69/LX4. The effect of CHA and AC on drug
accumulation was related to the GSH depletion, as we found a concentration-dependent relationship between the GSH levels and
the reversal of the accumulation deficit for both AC and CHA. To substantiate further this correlation, we increased cellular
GSH content in AC- and CHA-treated cells with the GSH ethyl ester. An increase in cellular GSH levels in CHA- and AC-treated
COR-L23/R cells was accompanied by a restoration of the DNR accumulation deficit. No significant effect of the GSH ethyl ester
was detected on DNR accumulation in COR-L23/P parental cells. In conclusion, treatment with AC or CHA can reverse the drug
accumulation deficit of MRP-overexpressing cells, and this effect appears to be mediated by GSH depletion. |
| format | Article |
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and ifosfamide. It has previously been reported that both metabolites can induce extensive depletion of glutathione (GSH)
in vitro and in vivo and that this depletion occurs at drug concentrations in the micromolar range. A link between the function
of the multidrug resistance-associated protein (MRP) and the intracellular concentration of GSH has also been demonstrated.
To determine whether AC and CHA can modulate the function of MRP by inducing GSH depletion, we used two human lung cancer
cell lines overexpressing MRP: the large cell carcinoma cell line COR-L23/R and the adenocarcinoma cell line MOR/R0.4, along
with their respective sensitive parental lines, COR-L23/P and MOR/P. We showed that micromolar concentrations of AC and millimolar
concentrations of CHA are able to deplete GSH concentrations in the cell lines studied. In addition, concentrations of 50
micrometer AC and 5 mm CHA could completely reverse the daunorubicin (DNR) and vinblastine accumulation deficit present in
COR-L23/R and partially reverse the DNR accumulation deficit in MOR/R0.4. In contrast, AC and CHA did not reverse the drug
accumulation deficit in the P-glycoprotein-overexpressing lung cancer cell line H69/LX4. The effect of CHA and AC on drug
accumulation was related to the GSH depletion, as we found a concentration-dependent relationship between the GSH levels and
the reversal of the accumulation deficit for both AC and CHA. To substantiate further this correlation, we increased cellular
GSH content in AC- and CHA-treated cells with the GSH ethyl ester. An increase in cellular GSH levels in CHA- and AC-treated
COR-L23/R cells was accompanied by a restoration of the DNR accumulation deficit. No significant effect of the GSH ethyl ester
was detected on DNR accumulation in COR-L23/P parental cells. In conclusion, treatment with AC or CHA can reverse the drug
accumulation deficit of MRP-overexpressing cells, and this effect appears to be mediated by GSH depletion.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>PMID: 9816303</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Acetaldehyde - analogs & derivatives ; Acetaldehyde - pharmacology ; Acrolein - pharmacology ; Antineoplastic agents ; ATP-Binding Cassette Transporters - physiology ; Biological and medical sciences ; Daunorubicin - pharmacokinetics ; Drug Resistance, Multiple ; General aspects ; Glutathione - analysis ; Humans ; Medical sciences ; Multidrug Resistance-Associated Proteins ; Pharmacology. Drug treatments ; Tumor Cells, Cultured ; Vinblastine - pharmacokinetics</subject><ispartof>Clinical cancer research, 1996-08, Vol.2 (8), p.1321-1326</ispartof><rights>1996 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3186295$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9816303$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>GONZALEZ MANZANO, R</creatorcontrib><creatorcontrib>WRIGHT, K. A</creatorcontrib><creatorcontrib>TWENTYMAN, P. R</creatorcontrib><title>Modulation by acrolein and chloroacetaldehyde of multidrug resistance mediated by the multidrug resistance-associated protein (MRP)</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Acrolein (AC) and chloroacetaldehyde (CHA) are metabolites of the non-multidrug resistance cytotoxic drugs cyclophosphamide
and ifosfamide. It has previously been reported that both metabolites can induce extensive depletion of glutathione (GSH)
in vitro and in vivo and that this depletion occurs at drug concentrations in the micromolar range. A link between the function
of the multidrug resistance-associated protein (MRP) and the intracellular concentration of GSH has also been demonstrated.
To determine whether AC and CHA can modulate the function of MRP by inducing GSH depletion, we used two human lung cancer
cell lines overexpressing MRP: the large cell carcinoma cell line COR-L23/R and the adenocarcinoma cell line MOR/R0.4, along
with their respective sensitive parental lines, COR-L23/P and MOR/P. We showed that micromolar concentrations of AC and millimolar
concentrations of CHA are able to deplete GSH concentrations in the cell lines studied. In addition, concentrations of 50
micrometer AC and 5 mm CHA could completely reverse the daunorubicin (DNR) and vinblastine accumulation deficit present in
COR-L23/R and partially reverse the DNR accumulation deficit in MOR/R0.4. In contrast, AC and CHA did not reverse the drug
accumulation deficit in the P-glycoprotein-overexpressing lung cancer cell line H69/LX4. The effect of CHA and AC on drug
accumulation was related to the GSH depletion, as we found a concentration-dependent relationship between the GSH levels and
the reversal of the accumulation deficit for both AC and CHA. To substantiate further this correlation, we increased cellular
GSH content in AC- and CHA-treated cells with the GSH ethyl ester. An increase in cellular GSH levels in CHA- and AC-treated
COR-L23/R cells was accompanied by a restoration of the DNR accumulation deficit. No significant effect of the GSH ethyl ester
was detected on DNR accumulation in COR-L23/P parental cells. In conclusion, treatment with AC or CHA can reverse the drug
accumulation deficit of MRP-overexpressing cells, and this effect appears to be mediated by GSH depletion.</description><subject>Acetaldehyde - analogs & derivatives</subject><subject>Acetaldehyde - pharmacology</subject><subject>Acrolein - pharmacology</subject><subject>Antineoplastic agents</subject><subject>ATP-Binding Cassette Transporters - physiology</subject><subject>Biological and medical sciences</subject><subject>Daunorubicin - pharmacokinetics</subject><subject>Drug Resistance, Multiple</subject><subject>General aspects</subject><subject>Glutathione - analysis</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Multidrug Resistance-Associated Proteins</subject><subject>Pharmacology. Drug treatments</subject><subject>Tumor Cells, Cultured</subject><subject>Vinblastine - pharmacokinetics</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkEtLAzEUhQdRaq3-BGEW4mMxkOQmzcxSxBe0KNL9kCZ3OpF0UpMM0rV_3CktrlzdC-fjHM45ysZUCFkAm4rj4SeyLAgHdpqdxfhJCOWU8FE2qko6BQLj7GfuTe9Usr7Ll9tc6eAd2i5Xncl163zwSmNSzmC7NZj7Jl_3LlkT-lUeMNqYVKcxX6OxKqHZeaQW_4UKFaPXe2wTfNrF3M4_3u_Os5NGuYgXhzvJFk-Pi4eXYvb2_PpwPytaNpWpYBVhjBIABCIakBVFLZRp-NIIygyXIA1roNIauBCcM0krCkvCsKSEVjDJrve2Q_hXjzHVaxs1Oqc69H2sZSklAOcDeHkA--VQrN4Eu1ZhWx9GG_Srg66iVq4JQzsb_zCg5ZRVYsBu9lhrV-23DVjr3QxhWARV0G3N6rKmwCj8AtBHhQs</recordid><startdate>19960801</startdate><enddate>19960801</enddate><creator>GONZALEZ MANZANO, R</creator><creator>WRIGHT, K. A</creator><creator>TWENTYMAN, P. R</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>19960801</creationdate><title>Modulation by acrolein and chloroacetaldehyde of multidrug resistance mediated by the multidrug resistance-associated protein (MRP)</title><author>GONZALEZ MANZANO, R ; WRIGHT, K. A ; TWENTYMAN, P. R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h267t-290221033e305f3791ec5adf4bd512d4737d2f39cc345544271913b02e810193</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Acetaldehyde - analogs & derivatives</topic><topic>Acetaldehyde - pharmacology</topic><topic>Acrolein - pharmacology</topic><topic>Antineoplastic agents</topic><topic>ATP-Binding Cassette Transporters - physiology</topic><topic>Biological and medical sciences</topic><topic>Daunorubicin - pharmacokinetics</topic><topic>Drug Resistance, Multiple</topic><topic>General aspects</topic><topic>Glutathione - analysis</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Multidrug Resistance-Associated Proteins</topic><topic>Pharmacology. Drug treatments</topic><topic>Tumor Cells, Cultured</topic><topic>Vinblastine - pharmacokinetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>GONZALEZ MANZANO, R</creatorcontrib><creatorcontrib>WRIGHT, K. A</creatorcontrib><creatorcontrib>TWENTYMAN, P. R</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>GONZALEZ MANZANO, R</au><au>WRIGHT, K. A</au><au>TWENTYMAN, P. R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Modulation by acrolein and chloroacetaldehyde of multidrug resistance mediated by the multidrug resistance-associated protein (MRP)</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>1996-08-01</date><risdate>1996</risdate><volume>2</volume><issue>8</issue><spage>1321</spage><epage>1326</epage><pages>1321-1326</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Acrolein (AC) and chloroacetaldehyde (CHA) are metabolites of the non-multidrug resistance cytotoxic drugs cyclophosphamide
and ifosfamide. It has previously been reported that both metabolites can induce extensive depletion of glutathione (GSH)
in vitro and in vivo and that this depletion occurs at drug concentrations in the micromolar range. A link between the function
of the multidrug resistance-associated protein (MRP) and the intracellular concentration of GSH has also been demonstrated.
To determine whether AC and CHA can modulate the function of MRP by inducing GSH depletion, we used two human lung cancer
cell lines overexpressing MRP: the large cell carcinoma cell line COR-L23/R and the adenocarcinoma cell line MOR/R0.4, along
with their respective sensitive parental lines, COR-L23/P and MOR/P. We showed that micromolar concentrations of AC and millimolar
concentrations of CHA are able to deplete GSH concentrations in the cell lines studied. In addition, concentrations of 50
micrometer AC and 5 mm CHA could completely reverse the daunorubicin (DNR) and vinblastine accumulation deficit present in
COR-L23/R and partially reverse the DNR accumulation deficit in MOR/R0.4. In contrast, AC and CHA did not reverse the drug
accumulation deficit in the P-glycoprotein-overexpressing lung cancer cell line H69/LX4. The effect of CHA and AC on drug
accumulation was related to the GSH depletion, as we found a concentration-dependent relationship between the GSH levels and
the reversal of the accumulation deficit for both AC and CHA. To substantiate further this correlation, we increased cellular
GSH content in AC- and CHA-treated cells with the GSH ethyl ester. An increase in cellular GSH levels in CHA- and AC-treated
COR-L23/R cells was accompanied by a restoration of the DNR accumulation deficit. No significant effect of the GSH ethyl ester
was detected on DNR accumulation in COR-L23/P parental cells. In conclusion, treatment with AC or CHA can reverse the drug
accumulation deficit of MRP-overexpressing cells, and this effect appears to be mediated by GSH depletion.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>9816303</pmid><tpages>6</tpages></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research; Alma/SFX Local Collection |
| subjects | Acetaldehyde - analogs & derivatives Acetaldehyde - pharmacology Acrolein - pharmacology Antineoplastic agents ATP-Binding Cassette Transporters - physiology Biological and medical sciences Daunorubicin - pharmacokinetics Drug Resistance, Multiple General aspects Glutathione - analysis Humans Medical sciences Multidrug Resistance-Associated Proteins Pharmacology. Drug treatments Tumor Cells, Cultured Vinblastine - pharmacokinetics |
| title | Modulation by acrolein and chloroacetaldehyde of multidrug resistance mediated by the multidrug resistance-associated protein (MRP) |
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