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, Shin Ichi Akiyama

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Abstract

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-hydroxycamptothecin, 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, (valine) 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 K(m) and V(max) 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 K(i) 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.

Original languageEnglish
Pages (from-to)1219-1228
Number of pages10
JournalMolecular Pharmacology
Volume56
Issue number6
DOIs
Publication statusPublished - 1999

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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    Chen, Z. S., Kawabe, T., Ono, M., Aoki, S., Sumizawa, T., Furukawa, T., Uchiumi, T., Wada, M., Kuwano, M., & Akiyama, S. I. (1999). Effect of multidrug resistance-reversing agents on transporting activity of human canalicular multispecific organic anion transporter. Molecular Pharmacology, 56(6), 1219-1228. https://doi.org/10.1124/mol.56.6.1219