ABCC2 p.Leu23Arg
| Predicted by SNAP2: | A: D (71%), C: D (66%), D: D (85%), E: D (85%), F: N (72%), G: D (80%), H: D (85%), I: N (57%), K: D (91%), M: D (66%), N: D (80%), P: D (85%), Q: D (80%), R: D (91%), S: D (80%), T: D (80%), V: N (66%), W: D (85%), Y: D (75%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: N, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: N, |
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[hide] Structural and functional properties of human mult... Curr Med Chem. 2011;18(3):439-81. He SM, Li R, Kanwar JR, Zhou SF
Structural and functional properties of human multidrug resistance protein 1 (MRP1/ABCC1).
Curr Med Chem. 2011;18(3):439-81., [PMID:21143116]
Abstract [show]
Multidrug ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1) and multidrug resistance protein 1 (MRP1/ABCC1) play an important role in the extrusion of drugs from the cell and their overexpression can be a cause of failure of anticancer and antimicrobial chemotherapy. Recently, the mouse P-gp/Abcb1a structure has been determined and this has significantly enhanced our understanding of the structure-activity relationship (SAR) of mammalian ABC transporters. This paper highlights our current knowledge on the structural and functional properties and the SAR of human MRP1/ABCC1. Although the crystal structure of MRP1/ABCC1 has yet to be resolved, the current topological model of MRP1/ABCC1 contains two transmembrane domains (TMD1 and TMD2) each followed by a nucleotide binding domain (NBD) plus a third NH2-terminal TMD0. MRP1/ABCC1 is expressed in the liver, kidney, intestine, brain and other tissues. MRP1/ABCC1 transports a structurally diverse array of important endogenous substances (e.g. leukotrienes and estrogen conjugates) and xenobiotics and their metabolites, including various conjugates, anticancer drugs, heavy metals, organic anions and lipids. Cells that highly express MRP1/ABCC1 confer resistance to a variety of natural product anticancer drugs such as vinca alkaloids (e.g. vincristine), anthracyclines (e.g. etoposide) and epipodophyllotoxins (e.g. doxorubicin and mitoxantrone). MRP1/ABCC1 is associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. However, most compounds that efficiently reverse P-gp/ABCB1-mediated multidrug resistance have only low affinity for MRP1/ABCC1 and there are only a few effective and relatively specific MRP1/ABCC1 inhibitors available. A number of site-directed mutagenesis studies, biophysical and photolabeling studies, SAR and QSAR, molecular docking and homology modeling studies have documented the role of multiple residues in determining the substrate specificity and inhibitor selectivity of MRP1/ABCC1. Most of these residues are located in the TMs of TMD1 and TMD2, in particular TMs 4, 6, 7, 8, 10, 11, 14, 16, and 17, or in close proximity to the membrane/cytosol interface of MRP1/ABCC1. The exact transporting mechanism of MRP1/ABCC1 is unclear. MRP1/ABCC1 and other multidrug transporters are front-line mediators of drug resistance in cancers and represent important therapeutic targets in future chemotherapy. The crystal structure of human MRP1/ABCC1 is expected to be resolved in the near future and this will provide an insight into the SAR of MRP1/ABCC1 and allow for rational design of anticancer drugs and potent and selective MRP1/ABCC1 inhibitors.
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No. Sentence Comment
335 Some other NSAIDs including sulindac were found to have a similar effect in human lung cancer cell lines DLKP, A549, COR L23P and COR L23R and in a human leukaemia line HL60/ADR [229], although it is unrelated to the action of these drugs on cyclooxygenases.
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ABCC2 p.Leu23Arg 21143116:335:134
status: NEW[hide] A new monoclonal antibody, P2A8(6), that specifica... Hybrid Hybridomics. 2001;20(5-6):333-41. Connolly L, Moran E, Larkin A, Scheffer G, Scheper R, Sarkadi B, Kool M, Clynes M
A new monoclonal antibody, P2A8(6), that specifically recognizes a novel epitope on the multidrug resistance-associated protein 1 (MRP1), but not on MRP2 nor MRP3.
Hybrid Hybridomics. 2001;20(5-6):333-41., [PMID:11839251]
Abstract [show]
Multidrug resistance (MDR) is a major problem in the chemotherapeutic treatment of cancer. Overexpression of the multidrug resistance-associated protein 1 (MRP1), is associated with MDR in certain tumors. A number of MRP1-specific MAbs, which facilitate both clinical and experimental investigations of this protein, are available. To add to this panel of existing antibodies, we have now generated an additional MRP1-specific monoclonal antibody (MAb), P2A8(6), which detects a unique heat stable epitope on the MRP1 molecule. Female Wistar rats were immunized via footpad injections with a combination of two short synthetic peptides corresponding to amino acids 235-246 (peptide A) and 246-260 (peptide B) of the MRP1 protein. Immune reactive B cells were then isolated from the popliteal lymph nodes for fusion with SP2/O-Ag14 myeloma cells. Resultant hybridoma supernatants were screened for MRP1-specific antibody production. Antibody P2A8(6) was characterized by Western blotting and immunocytochemistry on paired multidrug resistant (MRP1 overexpressing) and sensitive parental cell lines. The antibody detects a protein of 190 kDa in MRP1-expressing cell lines but not in MRP2- or MRP3-transfected cell lines. P2A8(6) stains drug-selected and MRP1-transfected cell lines homogeneously by immunocytochemistry and recognizes MRP1 by immunohistochemistry on formalin-fixed paraffin wax-embedded tissue sections. Peptide inhibition studies confirm that P2A8(6) reacts with peptide B (amino acids 246-260), therefore recognizing a different epitope from that of all currently available MRP1 MAbs. This new MAb, chosen for its specificity to the MRP1 protein, may be a useful addition to the currently available range of MRP1-specific MAbs.
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No. Sentence Comment
43 Control cell lines The multidrug resistant nonsmall cell lung carcinoma cell line, COR-L23R (made resistant by exposure to increasing concentrations of adriamycin(26)) and its drug-sensitive counterpart, COR-L23S, were used as control cells for the presence/absence of MRP1.
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ABCC2 p.Leu23Arg 11839251:43:87
status: NEW44 Overexpression of MRP1 in COR-L23R cells compared with the parental COR-L23S had been confirmed in previous studies using other commercially available antibodies raised against MRP1 (MRPr1, MRPm5, MRPm6,(15) QCRL-1, and QCRL-3(16)) (Alexis Biochemicals, San Diego, CA).
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ABCC2 p.Leu23Arg 11839251:44:30
status: NEW56 These supernatants were also screened by Western blot analysis, CONNOLLY ET AL.334 against cell membrane preparations of the MRP1-overexpressing COR-L23R cell line.
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ABCC2 p.Leu23Arg 11839251:56:150
status: NEW76 MAb P2A8(6) detects a 190-kDa band (associated with the presence of MRP1) on preparations from drug resistant cells (COR-L23R) and MRP1-transfected cells (2008 MRP1).
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ABCC2 p.Leu23Arg 11839251:76:121
status: NEW88 The antibody-peptide complex was centrifuged at 15,000 3 g in a microcentrifuge (Heraeus Instruments, Hanau, Germany) and the supernatantremoved carefully before use in Western blotting studies on COR-L23R cells.
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ABCC2 p.Leu23Arg 11839251:88:201
status: NEW91 Heat treatment appears to alter the expression of the antigen recognizedby MAb MRPr1 on the MRP1 protein expressed by the drug-resistant cells (COR-L23R).
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ABCC2 p.Leu23Arg 11839251:91:148
status: NEW96 Heat treatment does not appear to destroy the antigen recognized by MAb PA8(6) on the MRP1-drug resistant cells (COR-L23R) or MRP1-transfected cells (2008 MRP1).
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ABCC2 p.Leu23Arg 11839251:96:117
status: NEW102 MAb P2A8(6), like the well-characterized MRPr1 MAb, detects a 190-kDa band (associatedwith the presence of MRP1) in the COR-L23R and MRP1-transfected 2008 MRP1 cell lines.
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ABCC2 p.Leu23Arg 11839251:102:124
status: NEW103 These antibodies also detect a very low basal level of MRP1 expressed in the parental sensitiveCOR-L23R and parental nontransfected2008 cell lines.
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ABCC2 p.Leu23Arg 11839251:103:99
status: NEW109 Both MAbs detect MRP1 in the COR-L23R, HL60ADR, A549 and RPMI 2650 melphalan-selected cells.
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ABCC2 p.Leu23Arg 11839251:109:33
status: NEW115 MRP2 is undetectable in the COR-L23R, COR-L23S, HL60ADR, HL60S, DLKP, RPMI 2650, and RPMI 2650 taxol-selected cells.
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ABCC2 p.Leu23Arg 11839251:115:32
status: NEW117 MRP3 Heat treatment studies were carried out on the MRP1 overexpressing drug selected COR-L23R cell line and the MRP1-transfected cell line 2008 MRP1 prior to electrophoresis (cell lysates in loading buffer, placed in a water-bath for 3 min @ 100°C) (Figs.
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ABCC2 p.Leu23Arg 11839251:117:91
status: NEW119 These studies showed that heat treatment appears to decrease antigen recognition (observed mainly by a decrease in stainingintensityin the lower area of the MRP1 protein band on the Western blot) by the MRPr1 antibody in the drug-selectedCOR-L23R cell line.
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ABCC2 p.Leu23Arg 11839251:119:242
status: NEW121 The antigen recognized by antibody P2A8(6) appears to be heat stable in the drug selected COR-L23R cell line and the MRP1-transfected 2008 MRP1 cell line, as no decrease in staining intensity in the MRP1 protein band was observed following heat treatment (Fig. 4).
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ABCC2 p.Leu23Arg 11839251:121:94
status: NEW124 MRP1 expressionwas detectedby both these MAbs in the COR-L23R, HL60ADR, A549 and RPMI 2650 melphalan-selected cell lines.
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ABCC2 p.Leu23Arg 11839251:124:57
status: NEW134 SUMMARY OF MRP1, MRP2, AND MRP3 PROTEIN EXPRESSION LEVELS AS DETERMINED BY WESTERN BLOT ANALYSIS Protein expression levels (as determined by Western blot analysis) MRPr1 M2III-6 M3II-21 Cell line P2A8(6) (MRP1) (MRP2) (MRP3) COR-L23R 1 1 - - COR-L23S 1/2 1/2 - - HL60ADR 1 1 - - HL60S - - - - DLKP - - - - DLKPA - - - - A549 1 1 1 - RPMI 2650 - 1/2 - - Parental RPMI 2650 - - - - Taxol-selected RPMI 2650 1 1 1 - Melphalan-selected Key: -: Undetectable levels; 1: Over-expression; and 1/2: Very low basal levels.
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ABCC2 p.Leu23Arg 11839251:134:229
status: NEW139 Strong staining was seen on the non-Pgp MDR cell line COR-L23R and the MRP1-transfected 2008 ovarian carcinoma cell line but not their parental drug sensitive or nontransfected cell lines.
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ABCC2 p.Leu23Arg 11839251:139:58
status: NEW146 MAb P2A8(6) shows strong plasma-membranousstaining of the MRP1 overexpressingdrug selected cells (COR-L23R) and the MRP1-transfected cells (2008 MRP1).
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ABCC2 p.Leu23Arg 11839251:146:102
status: NEW[hide] Selection with melphalan or paclitaxel (Taxol) yie... Eur J Cancer. 2001 May;37(8):1041-52. Liang Y, Meleady P, Cleary I, McDonnell S, Connolly L, Clynes M
Selection with melphalan or paclitaxel (Taxol) yields variants with different patterns of multidrug resistance, integrin expression and in vitro invasiveness.
Eur J Cancer. 2001 May;37(8):1041-52., [PMID:11334731]
Abstract [show]
A melphalan-resistant variant (Roswell Park Memorial Institute (RPMI)-2650Ml) and a paclitaxel-resistant variant (RPMI-2650Tx) of the drug-sensitive human nasal carcinoma cell line, RPMI-2650, were established. The multidrug resistance (MDR) phenotype in the RPMI-2650Tx appeared to be P-glycoprotein (PgP)-mediated. Overexpression of multidrug resistant protein (MRP) family members was observed in the RPMI-2650Ml cells, which were also much more invasive in vitro than the parental cell line or the paclitaxel-resistant variant. Increased expression of alpha(2), alpha(5), alpha(6), beta(1) and beta(4) integrin subunits, decreased expression of alpha(4) integrin subunit, stronger adhesion to collagen type IV, laminin, fibronectin and matrigel, increased expression of MMP-2 and MMP-9 and significant motility compared with the parental cells were observed, along with a high invasiveness in the RPMI-2650Ml cells. Decreased expression of the alpha(2) integrin subunit, decreased attachment to collagen type IV, absence of cytokeratin 18 expression, no detectable expression of gelatin-degrading proteases and poor motility may be associated with the non-invasiveness of the RPMI-2650Tx variant. These results suggest that melphalan exposure can result in not only a MDR phenotype, but could also make cancer cells more invasive, whereas paclitaxel exposure resulted in MDR without increasing the in vitro invasiveness in the RPMI-2650 cells.
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No. Sentence Comment
135 Circumvention studies with verapamil and cyclosporin A The Pgp-overexpressing cell line DLKP-A and MRP1-overexpressing cell line COR-L23R were used as Fig. 1.
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ABCC2 p.Leu23Arg 11334731:135:133
status: NEW152 Table 3 Circumvention studies with verapamil and cyclosporin A in the RPMI-2650 cell line and its taxol- and melphalan-resistant variantsa Cell line IC50 (nM) ADR ADR+ verapamil (1 mg/ml) ADR+ cyclosporin A (1 mg/ml) COR-L23R 2097Æ364 938Æ146 1435Æ129 DLKP-A 5750Æ275 441Æ157 1582Æ167 RPMI-2650 110Æ37 59Æ18 77Æ19 RPMI-2650Tx 5750Æ224 2171Æ195 497Æ118 RPMI-2650Ml 690Æ138 48Æ15 304Æ125 ADR, doxorubicin.
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ABCC2 p.Leu23Arg 11334731:152:221
status: NEW136 Circumvention studies with verapamil and cyclosporin A The Pgp-overexpressing cell line DLKP-A and MRP1-overexpressing cell line COR-L23R were used as Fig. 1.
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ABCC2 p.Leu23Arg 11334731:136:133
status: NEW153 Table 3 Circumvention studies with verapamil and cyclosporin A in the RPMI-2650 cell line and its taxol- and melphalan-resistant variantsa Cell line IC50 (nM) ADR ADR+ verapamil (1 mg/ml) ADR+ cyclosporin A (1 mg/ml) COR-L23R 2097364 938146 1435129 DLKP-A 5750275 441157 1582167 RPMI-2650 11037 5918 7719 RPMI-2650Tx 5750224 2171195 497118 RPMI-2650Ml 690138 4815 304125 ADR, doxorubicin.
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ABCC2 p.Leu23Arg 11334731:153:221
status: NEW[hide] Budesonide reduces multidrug resistance-associated... Eur J Pharmacol. 2002 Feb 15;437(1-2):9-17. Bandi N, Kompella UB
Budesonide reduces multidrug resistance-associated protein 1 expression in an airway epithelial cell line (Calu-1).
Eur J Pharmacol. 2002 Feb 15;437(1-2):9-17., [PMID:11864633]
Abstract [show]
The objective of this study was to determine the expression and activity of multidrug resistance-associated protein (MRP1) in a human airway epithelial cell line (Calu-1) and to further assess whether budesonide, a potent antiasthma corticosteroid, alters the expression and activity of MRP1 in these cells. Reverse transcriptase polymerase chain reaction (RT-PCR) and the Western blot analysis demonstrated the MRP1 mRNA and MRP1 protein in Calu-1 cells. Indomethacin, probenecid, and verapamil significantly enhanced the fluorescein accumulation and reduced the fluorescein efflux, consistent with the MRP1 activity in the Calu-1 cells. Following 14-day budesonide treatment, fluorescein accumulation increased and fluorescein efflux decreased, consistent with the inhibition of MRP1 activity by budesonide. At a concentration (10 microM) devoid of cytotoxicity, budesonide treatment decreased MRP1 mRNA and MRP1 protein expression in Calu-1 cells by 38% and 42%, respectively. In addition, budesonide (10 microM) enhanced the sensitivity of the MRP1 overexpressing COR-L23R cells to vincristine, suggesting the chemosensitizing effect of budesonide. Thus, budesonide inhibits MRP1 expression and may be useful as a chemosensitizer in tumor chemotherapy.
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No. Sentence Comment
67 The doxorubicin-resistant COR-L23R cells used as the MRP1 positive controls in the Western blot and vincristine sensitivity studies were N. Bandi, U.B. Kompella / European Journal of Pharmacology 437 (2002) 9-1710 obtained from Dr. Donald W. Miller (Nebraska Medical Center, Omaha, NE).
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ABCC2 p.Leu23Arg 11864633:67:30
status: NEW81 Cell lysates of the human lung carcinoma cells, COR-L23R, used as MRP1 positive controls (Thomas et al., 1994) in the Western blot analysis, were loaded at 10-mg protein.
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ABCC2 p.Leu23Arg 11864633:81:52
status: NEW125 In this study, MRP1 overexpressing COR-L23R cells seeded at densities of 5000 cells/well in 96-well plates were treated with various concentrations of vincristine (0.1-5 nM) with or without budesonide (10 mM).
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ABCC2 p.Leu23Arg 11864633:125:39
status: NEW188 * Indicates significant difference from controls in the accumulation and efflux studies. Fig. 6. Effect of the budesonide on the vincristine-mediated cytotoxicity in the COR-L23R cells.
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ABCC2 p.Leu23Arg 11864633:188:174
status: NEW189 The sensitivity of the COR-L23R cells to the vincristine was determined in the presence and absence of budesonide (10 mM) using an MTT assay.
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ABCC2 p.Leu23Arg 11864633:189:27
status: NEW222 In order to determine whether budesonide enhances the chemosensitivity of anticancer drugs, we determined the cytotoxic effects of vincristine with and without budesonide in COR-L23R cells.
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ABCC2 p.Leu23Arg 11864633:222:178
status: NEW224 The results of our study indicated that budesonide, at concentrations devoid of cytotoxicity (Table 1a), enhanced the sensitivity of COR-L23R to vincristine (Fig. 6), possibly by inhibiting MRP1 expression.
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ABCC2 p.Leu23Arg 11864633:224:137
status: NEW226 However, as the vincristine studies were performed in MRP1 overexpressing COR-L23R cells, we believe that our results are consistent with the inhibition of the MRP1-mediated efflux of vincristine.
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ABCC2 p.Leu23Arg 11864633:226:78
status: NEW191 * Indicates significant difference from controls in the accumulation and efflux studies. Fig. 6. Effect of the budesonide on the vincristine-mediated cytotoxicity in the COR-L23R cells.
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ABCC2 p.Leu23Arg 11864633:191:174
status: NEW192 The sensitivity of the COR-L23R cells to the vincristine was determined in the presence and absence of budesonide (10 mM) using an MTT assay.
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ABCC2 p.Leu23Arg 11864633:192:27
status: NEW225 In order to determine whether budesonide enhances the chemosensitivity of anticancer drugs, we determined the cytotoxic effects of vincristine with and without budesonide in COR-L23R cells.
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ABCC2 p.Leu23Arg 11864633:225:178
status: NEW227 The results of our study indicated that budesonide, at concentrations devoid of cytotoxicity (Table 1a), enhanced the sensitivity of COR-L23R to vincristine (Fig. 6), possibly by inhibiting MRP1 expression.
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ABCC2 p.Leu23Arg 11864633:227:137
status: NEW229 However, as the vincristine studies were performed in MRP1 overexpressing COR-L23R cells, we believe that our results are consistent with the inhibition of the MRP1-mediated efflux of vincristine.
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ABCC2 p.Leu23Arg 11864633:229:78
status: NEW