Document Detail

Effect of multidrug resistance-reversing agents on transporting activity of human canalicular multispecific organic anion transporter.
MedLine Citation:
PMID:  10570049     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular pharmacology     Volume:  56     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  1999 Dec 
Date Detail:
Created Date:  1999-12-17     Completed Date:  1999-12-17     Revised Date:  2010-01-04    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1219-28     Citation Subset:  IM    
Department of Cancer Chemotherapy, Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Sakuragaoka Kagoshima, Japan.
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MeSH Terms
Adenosine Triphosphate / metabolism
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
Leukotriene C4 / metabolism
Nicotinic Acids / pharmacology*
Osmolar Concentration
Propionates / pharmacology
Quinolines / pharmacology
Vincristine / pharmacology
Reg. No./Substance:
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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