| Effect of multidrug resistance-reversing agents on transporting activity of human canalicular multispecific organic anion transporter. | |
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MedLine Citation:
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PMID: 10570049 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The canalicular multispecific organic anion transporter (cMOAT), also termed MRP2, is a recently identified ATP-binding cassette transporter. We previously established stable human cMOAT cDNA-transfected cells, LLC/cMOAT-1 from LLC-PK1 cells, and LLC/CMV cells that were transfected with an empty vector. We found that LLC/cMOAT-1 cells have increased resistance to vincristine (VCR), 7-ethyl-10-hydroxy-camptothecin, and cisplatin but not to etoposide. The multidrug resistance-reversing agents cyclosporin A (CsA) and 2-[4-(diphenylmethyl)-1-piperazinyl]-5-(trans-4,6-dimethyl-1,3, 2-dioxaphosphorinan-2-yl)-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate P-oxide (PAK-104P) almost completely reversed the resistance to VCR, 7-ethyl-10-hydroxy-camptothecin, and cisplatin of LLC/cMOAT-1 cells; and DL-buthionine-(S,R)-sulfoximine, (3'-oxo-4-butenyl-4-methyl-threonine(1), (valine(2)) cyclosporin (PSC833), and 3-([(3-(2-[7-chloro-2-quinolinyl]ethenyl)phenyl)-((3-dimethylamino-3- oxopropyl)-thio)-methyl]thio)propanoic acid (MK571) partially reversed the resistance to these drugs. CsA and PAK-104P at 10 microM enhanced the accumulation of VCR in LLC/cMOAT-1 cells almost to the level in LLC/CMV cells without the agents. The efflux of VCR from LLC/cMOAT-1 cells was enhanced compared with LLC/CMV cells and inhibited by CsA and PAK-104P. Transport of leukotriene C(4) (LTC(4)) and S-(2, 4-dinitrophenyl)glutathione also was studied with membrane vesicles prepared from these cells. LTC(4) and S-(2, 4-dinitrophenyl)glutathione were actively transported into membrane vesicles prepared from LLC/cMOAT-1 cells. The K(m) and V(max) values for the uptake of LTC(4) by the LLC/cMOAT-1 membrane vesicles were 0. 26 +/- 0.05 microM and 7.48 +/- 0.67 pmol/min/mg protein, respectively. LTC(4) transport was competitively inhibited by PAK-104P, CsA, MK571, and PSC833, with K(i) values of 3.7, 4.7, 13.1, and 28.9 microM, respectively. These findings demonstrate that cMOAT confers a novel drug-resistance phenotype. CsA and PAK-104P may be useful for reversing cMOAT-mediated drug resistance in tumors. |
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Authors:
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Z S Chen; T Kawabe; M Ono; S Aoki; T Sumizawa; T Furukawa; T Uchiumi; M Wada; M Kuwano; S I Akiyama |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Molecular pharmacology Volume: 56 ISSN: 0026-895X ISO Abbreviation: Mol. Pharmacol. Publication Date: 1999 Dec |
Date Detail:
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Created Date: 1999-12-17 Completed Date: 1999-12-17 Revised Date: 2010-01-04 |
Medline Journal Info:
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Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 1219-28 Citation Subset: IM |
Affiliation:
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Department of Cancer Chemotherapy, Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Sakuragaoka Kagoshima, Japan. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphate
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metabolism Animals Anion Transport Proteins Antineoplastic Agents / pharmacology Biological Transport / drug effects Carrier Proteins / drug effects, genetics, metabolism* Cells, Cultured Cyclic P-Oxides / pharmacology* Cyclosporine / pharmacology* Drug Interactions Drug Resistance, Multiple / physiology* Glutathione / analogs & derivatives, metabolism Humans Kinetics Leukotriene C4 / metabolism Nicotinic Acids / pharmacology* Osmolar Concentration Propionates / pharmacology Quinolines / pharmacology Swine Transfection Tritium Vincristine / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Anion Transport Proteins; 0/Antineoplastic Agents; 0/Carrier Proteins; 0/Cyclic P-Oxides; 0/Nicotinic Acids; 0/Propionates; 0/Quinolines; 10028-17-8/Tritium; 115104-28-4/verlukast; 131356-86-0/PAK 104P; 26289-39-4/S-(2,4-dinitrophenyl)glutathione; 56-65-5/Adenosine Triphosphate; 57-22-7/Vincristine; 59865-13-3/Cyclosporine; 70-18-8/Glutathione; 72025-60-6/Leukotriene C4 |
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