Transport of the glutathione conjugate of ethacrynic acid by the human multidrug resistance protein MRP

Zaman, Guido J.R.; Cnubben, N.H.P.; Bladeren, P.J. van; Evers, Raymond; Borst, Piet

doi:10.1016/0014-5793(96)00718-1

Cited by 61 publications

(58 citation statements)

References 24 publications

(47 reference statements)

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“…This implies that ethacrynic acid may modulate drug resistance of tumor cells not only by inhibiting glutathione S-transferase activity, but also by inhibiting the export of drug conjugate from the cell by MRP1. 68 Indomethacin is also reported as a specific inhibitor of MRP1 possibly functioning also by inhibition of glutathione-S-transferase or, alternatively, by direct competition with the drug at the transport site. 69 Pyridine analog, [2[4-…”

Section: Mrp1 Activity In Amlmentioning

confidence: 99%

Role of MRP1 in multidrug resistance in acute myeloid leukemia

1999

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The best characterized resistance mechanism in adult acute myeloid leukemia (AML) is the one mediated by the MDR1 gene which has been shown to be associated with poor outcome. However, alternative proteins such as the more recently recognized multidrug-associated protein (MRP1), may also contribute to the resistance to anthracyclines and etoposide in AML. Recently, the role of this protein was discussed and was unclear in AML. However, recent data concerning the functionality and the modulation of the activity of MRP1 may elucidate its role in comparison with other mechanisms of resistance. In this paper, we will review these recent data concerning the role of MRP1 in adult AML.

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Section: Mrp1 Activity In Amlmentioning

confidence: 99%

Role of MRP1 in multidrug resistance in acute myeloid leukemia

1999

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“…5 In the present work, we show the cytotoxic activity of four NBD derivatives on cell lines deriving from different sources, describing in detail the apoptotic process induced by the selected derivative 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) in human leukemic K562 and CCRF-CEM cell lines. The new GST inhibitor triggers apoptosis by the activation of the JNK/c-Jun-mediated pathway.…”

Section: Introductionmentioning

confidence: 99%

“…They are involved in the detoxification of cells from many endogenous and xenobiotic compounds by catalysing their conjugation to the tripeptide glutathione (GSH). Many anticancer drugs are substrates for the GST and thus they can be conjugated with the GSH and efficiently extruded from the cell by specific export pumps (2)(3)(4)(5). Therefore, the overexpression of GSTs in the tumor cell lines, in particular of GSTP1-1, is responsible for their resistance to certain chemotherapeutic drugs (6,7).…”

Section: Introductionmentioning

confidence: 99%

“…

AbstractSelected 7-nitro-2,1,3-benzoxadiazole derivatives have been recently found very efficient inhibitors of glutathione Stransferase (GST) P1-1, 5 an enzyme which displays antiapoptotic activity and is also involved in the cellular resistance to anticancer drugs. These new inhibitors are not tripeptide glutathione-peptidomimetic molecules and display lipophylic properties suitable for crossing the plasma membrane.

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confidence: 99%

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Proapoptotic Activity of New Glutathione S-Transferase Inhibitors

Turella¹,

et al. 2005

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Selected 7-nitro-2,1,3-benzoxadiazole derivatives have been recently found very efficient inhibitors of glutathione Stransferase (GST) P1-1, 5 an enzyme which displays antiapoptotic activity and is also involved in the cellular resistance to anticancer drugs. These new inhibitors are not tripeptide glutathione-peptidomimetic molecules and display lipophylic properties suitable for crossing the plasma membrane. In the present work, we show the strong cytotoxic activity of these compounds in the following four different cell lines: K562

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“…P-glycoprotein transports these drugs in unmodified form, whereas MRP1 can transport drugs either conjugated to anionic ligands such as glutathione (GSH), glucuronide, or sulfate, or in an unmodified form, possibly together with GSH. Well known substrates for MRP1 are, for example, cysteinyl leukotrienes, glutathione disulfide, S- (2,4-dinitrophenyl-)glutathione, ethacrynic acid S-glutathione, etoposide glucuronide, certain steroid glucuronides, and bile salt derivatives (3)(4)(5)(6). Transporters with the characteristics of MRP1 are known as GS-X pumps (7) or multispecific organic anion transporters (8).…”

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confidence: 99%

MRP3, an organic anion transporter able to transport anti-cancer drugs

Kool

Linden

Haas

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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585

429

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The human multidrug-resistance protein (MRP) gene family contains at least six members: MRP1, encoding the multidrug-resistance protein; MRP2 or cMOAT, encoding the canalicular multispecific organic anion transporter; and four homologs, called MRP3, MRP4, MRP5, and MRP6. In this report, we characterize MRP3, the closest homolog of MRP1. Cell lines were retrovirally transduced with MRP3 cDNA, and new monoclonal antibodies specific for MRP3 were generated. We show that MRP3 is an organic anion and multidrug transporter, like the GS-X pumps MRP1 and MRP2. In Two members of the large family of ABC transporters are known thus far to confer multidrug resistance in human cancer cells. These are the MDR1 P-glycoprotein (1) and the multidrugresistance protein MRP1 (2). Both membrane proteins transport a wide range of drugs with different cellular targets and confer resistance by decreasing the intracellular concentration of drugs. P-glycoprotein transports these drugs in unmodified form, whereas MRP1 can transport drugs either conjugated to anionic ligands such as glutathione (GSH), glucuronide, or sulfate, or in an unmodified form, possibly together with GSH. Well known substrates for MRP1 are, for example, cysteinyl leukotrienes, glutathione disulfide, S-(2,4-dinitrophenyl-)glutathione, ethacrynic acid S-glutathione, etoposide glucuronide, certain steroid glucuronides, and bile salt derivatives (3-6). Transporters with the characteristics of MRP1 are known as GS-X pumps (7) or multispecific organic anion transporters (8).Another GS-X pump is MRP2, a homolog of MRP1. Unlike MRP1, which is nearly ubiquitously expressed (9), MRP2 is present mainly in the canalicular membrane of hepatocytes (10), but is also present in other apical domains of polarized cells such as the epithelial cells of the proximal tubules of the kidney (11). Studies with mutant rats (TR Ϫ ͞GY or EHBR), which lack the MRP2 protein in the canalicular membrane of hepatocytes, have shown that the substrate specificity of MRP2 is very similar to that of MRP1 (12, 13). MRP2 also contributes to transport of anticancer drugs and some metals. The mutant rats showed a reduced biliary clearance of methotrexate (14), of the topoisomerase I inhibitor CPT-11 and its metabolites (15), and of mercury, cadmium, and arsenite (refs. 16 and 17; R.O.E., unpublished observation). Cells transduced with an MRP2 cDNA construct transport the cytostatic drug vinblastine (18). Moreover, overexpression of the MRP2 gene has been found in several cisplatinresistant cell lines (19,20), and transfection of an MRP2-antisense construct into liver cells was reported to confer an increased sensitivity to cytotoxic drugs (21). All these observations strongly suggest that MRP2 may confer multidrug resistance, but whether it does so in cancer patients remains to be established.Besides MRP1 and MRP2, there are at least four MRP homologs expressed in humans, called MRP3, MRP4, MRP5, and MRP6 (20,22). Not much is known about the substrate specificity of these putative new transporters...

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Transport of the glutathione conjugate of ethacrynic acid by the human multidrug resistance protein MRP

Cited by 61 publications

References 24 publications

Role of MRP1 in multidrug resistance in acute myeloid leukemia

Role of MRP1 in multidrug resistance in acute myeloid leukemia

Proapoptotic Activity of New Glutathione S-Transferase Inhibitors

MRP3, an organic anion transporter able to transport anti-cancer drugs

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