The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump.

Abstract

The multidrug-resistance associated protein MRP is a 180-to 195-kDa membrane protein associated with resistance of human tumor cells to cytotoxic drugs. We have investigated how MRP confers drug resistance in SW-1573 human lung carcinoma cells by generating a subline stably transfected with an expression vector containing MRP cDNA. MRP-overexpressing SW-1573 cells are resistant to doxorubicin, daunorubicin, vincristine, VP-16, colchicine, and rhodamine 123, but not to 4'-(9-acridinylamino)methanesulfon-manisidide or taxol. The intracellular accumulation of drug (daunorubicin, vincristine, (20) and pRc/RSV (Invitrogen). All cDNA fragments used for the assembly of the MRP cDNA were sequenced and the integrity of the MRP cDNA fragment in the resulting expression vectors, pJ3fl-MRP and pRc/RSV-MRP (Fig. 1) Abbreviations: MDR, multidrug resistance (resistant); Pgp, P-glycoprotein; SCLC, small-cell lung cancer; pH;, intracellular pH; m-AMSA, 4'-(9-acridinylamino)methanesulfon-m-anisidide. 8822The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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

“…SI(MRP) is a subline of the human non-small cell lung cancer cell line SW-1573/S1 that overexpresses MRP 15-fold [3,8]. This cell line was obtained by transfection of S1 ceils with an expression vector containing MRP cDNA and a neomycin-resistance gene and selection with Geneticin (G418) [3].…”

“…This cell line was obtained by transfection of S1 ceils with an expression vector containing MRP cDNA and a neomycin-resistance gene and selection with Geneticin (G418) [3]. GLC4/ADR is a subline of the human small cell lung cancer cell line GLC4 that overexpresses MRP 51~ 100-fold [3,5].…”

“…GLC4/ADR is a subline of the human small cell lung cancer cell line GLC4 that overexpresses MRP 51~ 100-fold [3,5]. This cell line was isolated by a multistep selection of GLC4 cells up to 1152 nM doxorubicin [3,5]. The yeast strain DTY168 (Mato~, ura3-52, ycflA::his, leu2-3, -112, his6) [25] was used for heterologous expression of the MRP cDNA [6], (109 cells) were washed twice, scraped into ice-cold phosphate-buffered saline (PBS) and collected by centrifugation at 1000×g for 10 rain at 4°C, GLC4 and GLC4/ADR cells were harvested by centrifugation and washed twice with PBS.…”

“…The human multidrug resistance-associated protein MRP confers resistance to natural product drugs by lowering their intracellular concentration [1][2][3]. Although the resistance spectrum of MRP resembles that of MDR1 P-glycoprotein (Pgp), there are several indications that the mechanism of drug transport by MRP is fundamentally different from that of Pgp.…”

“…(iii) Drug transport by MRP is relatively insensitive to classic reversal agents of Pgp-mediated multidrug resistance (MDR), such as verapamil and cyclosporin (analogues) [2,3], but is modulated by inhibitors of organic anion transport, such as probenecid and sulfinpyrazone [6,7,9,10]. These data suggest that MRP is a GS-X pump [I1] and link MRP-mediated MDR to drug resistance associated with GSH and GSH S-transferases (GSTs) [5,8,12].…”