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Vol. 56, Issue 6, 1219-1228, December 1999

Effect of Multidrug Resistance-Reversing Agents on Transporting Activity of Human Canalicular Multispecific Organic Anion Transporter

Zhe-Sheng Chen, Takeshi Kawabe, Mayumi Ono, Shunji Aoki, Tomoyuki Sumizawa, Tatsuhiko Furukawa, Takeshi Uchiumi, Morimasa Wada, Michihiko Kuwano, and Shin-Ichi Akiyama

Department of Cancer Chemotherapy, Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Sakuragaoka Kagoshima (Z-S.C., T.S., T.F., S.A.); Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka (T.K., M.O., T.U., M.W., M.K.); and Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (S.A.)

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-threonine1, (valine2) 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 µM 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 C4 (LTC4) and S-(2, 4-dinitrophenyl)glutathione also was studied with membrane vesicles prepared from these cells. LTC4 and S-(2, 4-dinitrophenyl)glutathione were actively transported into membrane vesicles prepared from LLC/cMOAT-1 cells. The Km and Vmax values for the uptake of LTC4 by the LLC/cMOAT-1 membrane vesicles were 0.26 ± 0.05 µM and 7.48 ± 0.67 pmol/min/mg protein, respectively. LTC4 transport was competitively inhibited by PAK-104P, CsA, MK571, and PSC833, with Ki values of 3.7, 4.7, 13.1, and 28.9 µM, 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.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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