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

研究成果: ジャーナルへの寄稿記事

152 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)1219-1228
ページ数10
ジャーナルMolecular Pharmacology
56
発行部数6
DOI
出版物ステータス出版済み - 1 1 1999

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Multiple Drug Resistance
Human Activities
Cyclosporine
Leukotriene C4
Vincristine
Drug Resistance
irinotecan
Cisplatin
Membranes
multidrug resistance-associated protein 2
LLC-PK1 Cells
Camptothecin
ATP-Binding Cassette Transporters
Valine
Etoposide
Threonine
Oxides
Complementary DNA
PAK 104P
Phenotype

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

これを引用

Effect of multidrug resistance-reversing agents on transporting activity of human canalicular multispecific organic anion transporter. / Chen, Zhe Sheng; Kawabe, Takeshi; Ono, Mayumi; Aoki, Shunji; Sumizawa, Tomoyuki; Furukawa, Tatsuhiko; Uchiumi, Takeshi; Wada, Morimasa; Kuwano, Michihiko; Akiyama, Shin Ichi.

:: Molecular Pharmacology, 巻 56, 番号 6, 01.01.1999, p. 1219-1228.

研究成果: ジャーナルへの寄稿記事

Chen, ZS, Kawabe, T, Ono, M, Aoki, S, Sumizawa, T, Furukawa, T, Uchiumi, T, Wada, M, Kuwano, M & Akiyama, SI 1999, 'Effect of multidrug resistance-reversing agents on transporting activity of human canalicular multispecific organic anion transporter', Molecular Pharmacology, 巻. 56, 番号 6, pp. 1219-1228. https://doi.org/10.1124/mol.56.6.1219
Chen, Zhe Sheng ; Kawabe, Takeshi ; Ono, Mayumi ; Aoki, Shunji ; Sumizawa, Tomoyuki ; Furukawa, Tatsuhiko ; Uchiumi, Takeshi ; Wada, Morimasa ; Kuwano, Michihiko ; Akiyama, Shin Ichi. / Effect of multidrug resistance-reversing agents on transporting activity of human canalicular multispecific organic anion transporter. :: Molecular Pharmacology. 1999 ; 巻 56, 番号 6. pp. 1219-1228.
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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.",
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T1 - Effect of multidrug resistance-reversing agents on transporting activity of human canalicular multispecific organic anion transporter

AU - Chen, Zhe Sheng

AU - Kawabe, Takeshi

AU - Ono, Mayumi

AU - Aoki, Shunji

AU - Sumizawa, Tomoyuki

AU - Furukawa, Tatsuhiko

AU - Uchiumi, Takeshi

AU - Wada, Morimasa

AU - Kuwano, Michihiko

AU - Akiyama, Shin Ichi

PY - 1999/1/1

Y1 - 1999/1/1

N2 - 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.

AB - 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.

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