Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The multidrug resistant cell lines HL60/AR and GLC4/ADR show high overexpression of the gene encoding the multidrug resistance associated protein MRP compared to their drug sensitive parental counterparts. This and the virtual absence of mdr1/P-glycoprotein gene expression was proven by a complementary DNA polymerase chain reaction (cDNA-PCR) approach. Applying a 72-hour tetrazolium based colorimetric MTT-assay we demonstrate on both MDR sublines a dose-dependent modulation of drug resistances by the leukotriene LTD4 receptor antagonist MK571. A complete reversal of vincristine resistances was achieved at final MK571 concentrations of 30 microM (HL60/AR) or 50 microM (GLC4/ADR) which by itself did not disturb cellular proliferation. The drug resistance of a mdr1/P-gp overexpressing multidrug-resistant HL60 subline, in contrast, was not significantly affected by MK571. Similar effects were seen using the glutathione (GSH) synthesis inhibitor buthionine sulfoximine (BSO). Our results point to a relationship between MRP and a conjugate transporter and identify MK571 as a new tool structure for developing modulators specific for a MRP associated multidrug resistance.
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PMID:The leukotriene LTD4 receptor antagonist MK571 specifically modulates MRP associated multidrug resistance. 788 49

We have investigated the effects of H(+)-ATPase inhibitors, bafilomycin A1 and 7-chloro-4-nitro-benz-2-oxa-1,3 diazole (NBD), and the Golgi inhibitor, brefeldin A, on daunorubicin accumulation and doxorubicin intracellular distribution in the non-P-glycoprotein-mediated multidrug-resistant cell line COR-L23/R. This cell line overexpress a 190 kDa protein which is probably the product of the MRP gene and shows an anthracycline accumulation defect and a drastically altered intracellular anthracycline distribution from the parental cell line COR-L23/P. We found that all three agents could selectively increase the cellular accumulation of daunorubicin in resistant cells. However, these effects were only seen at doses of the modifiers which were equal to or greater than the IC50 of the modifier alone. Effects of the modifiers on the intracellular distribution of doxorubicin fluorescence could, however, be seen at doses lower than those required to produce significant effects on daunorubicin accumulation. However, when used in a continuous MTT chemosensitivity assay none of the agents, used at maximum non-toxic doses, was able to sensitise COR-L23/R cells to doxorubicin or to colchicine. Although these lead compounds are unlikely to be useful as clinical modifiers, development of more selective analogues may prove useful in the modification of non-P-glycoprotein-mediated multidrug resistance.
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PMID:Modification by brefeldin A, bafilomycin A1 and 7-chloro-4-nitrobenz-2-oxa-1,3-diazole (NBD) of cellular accumulation and intracellular distribution of anthracyclines in the non-P-glycoprotein-mediated multidrug-resistant cell line COR-L23/R. 791 44

Multiple drug resistance(MDR) is a major clinical obstacle in cancer chemotherapy. Acquirement of MDR phenotype in cancer cells is often associated with enhanced expression of human MDR-1 gene: MDR-1 gene codes membranous P-glycoprotein which catalyses energy-dependent outward transport of anticancer agents. By contrast, MDR cancer cell lines without overexpression of P-glycoprotein are called as atypical MDR (at MDR) cells. The acquirement of at MDR has been shown to be partly associated with altered DNA topoisomerase II. Furthermore, a new ATP binding cassette (ABC) family, MRP gene has just recently shown to involve in acquirement of at-MDR in cancer cell lines, which do not express both altered topoisomerase II and P-glycoprotein.
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PMID:[Atypical MDR]. 791 11

The induced expression of multiple drug resistance (MDR)-associated genes as a direct response of tumor cells to antineoplastic drugs could be an important factor influencing the success of cancer chemotherapy. We investigated the effects of such compounds on mdr1/P-glycoprotein (P-gp) gene expression and drug sensitivities in the T-lymphoblastoid human cell line CCRF-CEM and MDR sublines. Thereby, we observed that actinomycin D or adriamycin administered at sublethal concentrations induced increases of mdr1 mRNA levels and resistance within 72 h. Furthermore, on leukemia cell samples collected before and after chemotherapy we checked by a complementary DNA polymerase chain reaction (cDNA-PCR) approach for similar alterations in the relative expression levels of the MDR-associated genes (a) mdr1/P-gp (b) mrp (MDR related protein), and (c) the topoisomerase II isoforms alpha and beta. We found a concomitant increase in mdr1 and mrp gene expression combined with a decreased expression of topoisomerase II alpha in the course of the second relapse of an acute lymphoblastic leukemia (ALL). This points to the emergence of at least three different MDR mechanisms in this type of leukemia unresponsive to chemotherapy. A chronic myeloid leukemia (CML) in blast crisis, however, showed combined increases in mdr1 (about 20-fold) and mrp (about four fold) gene expression after intense but unsuccessful chemotherapy over a 6-month period. Our results indicate the occurrence of induced resistance in vitro and in vivo and suggest a contribution of the newly identified ATP-binding cassette (ABC) transporter MRP in MDR.
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PMID:Drug-induced changes in the expression of MDR-associated genes: investigations on cultured cell lines and chemotherapeutically treated leukemias. 791 48

The MRP gene (Cole et al., Science (Washington DC), 258: 1650-1654, 1992) encodes a membrane-bound glycoprotein the expression of which correlates with non-P-glycoprotein-mediated multidrug resistance in a variety of cultured human cell lines. Using an RNA-polymerase chain reaction assay, expression of this gene was examined in the highly chemoresistant pediatric malignancy, neuroblastoma. MRP expression was observed in 5 human neuroblastoma cell lines and in all 25 primary neuroblastoma tumors of stage I through IVS. Tumors with amplification of the N-myc oncogene were found to have significantly higher MRP expression that those with no amplification (P = 0.0016). Expression of the MRP gene in the tumor specimens was highly correlated with expression of the N-myc gene (P = 0.0009), while expression of the MDR1 gene, encoding P-glycoprotein, was not related to expression of either the N-myc or MRP genes. Decreased expression of the N-myc oncogene in neuroblastoma cell lines SH-SY5Y and BE(2)-C, following treatment with retinoic acid, was paralleled by down-regulation of MRP gene expression, contrasting with increased expression of the MDR1 gene. Expression of the MRP gene is thus common in both primary neuroblastoma tumors and cultured cell lines, and correlates with amplification and overexpression of the N-myc oncogene, which is central to the malignant phenotype of this disease.
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PMID:Expression of the multidrug resistance-associated protein (MRP) gene correlates with amplification and overexpression of the N-myc oncogene in childhood neuroblastoma. 792 12

In an effort to define clearly the basis of non-P-glycoprotein multidrug resistance in HL60/ADR cells, we have analyzed expression of MRP mRNA levels and the MRP-encoded protein in resistant cells and also in resistant cells that have undergone a reversion to drug sensitivity. The results demonstrate that an MRP cDNA containing 5'-end coding sequences reacts with a 6-kb RNA, which is overexpressed in the resistant isolate. As resistant cells revert to drug sensitivity there is essentially a complete loss of the 6-kb RNA. Southern blot analysis indicates that the MRP gene is amplified compared to the copy number found in sensitive cells. Revertant cells no longer contain amplified MRP sequences. Western blot analysis has been conducted using an antibody prepared against the carboxyl terminus (15 amino acids) of the deduced sequence of the MRP-encoded protein. The antibody is reactive with a 190-kDa protein (P190) and with two closely migrating proteins of 65 and 70 kDa (P70), which are overexpressed in plasma membranes and endoplasmic reticulum of resistant cells. Both proteins are greatly reduced in revertant cells. Growth of cells in the presence of tunicamycin demonstrates that both P190 and P70 are glycosylated, with the deglycosylated forms migrating in polyacrylamide gels as proteins of 165 kDa and 45 kDa, respectively. Additional antisera have also been prepared against sequence domains contained in the C-terminal region of P190. These antisera are reactive with both P190 and P70. Antisera directed against sequences of the amino terminal region of P190 do not react with P70.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Analysis of MRP gene expression and function in HL60 cells isolated for resistance to adriamycin. 799 83

Multiple drug resistance (MDR) is a major problem of current chemotherapy. Establishment of multiple drug resistant cell lines in culture and isolation of P-glycoprotein-coding MDR genes have promoted understanding of the molecular mechanisms underlying drug resistance in tumors. Another gene, MRP, has been recently isolated from a multiple drug resistant cell line which did not express P-glycoprotein. Both genes have DNA sequence homology for each other and have been identified as members of ATP binding cassette (ABC) transporter superfamily. This review refers to recent progress in MDR and MRP study, and focuses on involvement of these two drug-resistance-related genes in acquiring drug resistance and their physiological functions.
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PMID:[Multidrug resistance (MDR)]. 800 31

Non-P-glycoprotein multidrug resistance of HL60/ADR cells appears to be related to overexpression of the MRP gene. Recent studies suggest that this gene may play an important role in a new form of cell resistance to certain chemotherapeutic agents. To examine mechanisms regulating transcriptional activity of this gene, a 2.2-kilobase 5'-flanking sequence of MRP has been isolated from a genomic library prepared from HL60/ADR cells. The 2.2-kilobase DNA fragment linked to the chloramphenicol acetyltransferase (CAT) gene in a reporter plasmid was found to be capable of driving expression of this gene in transient transfection experiments. This DNA containing promoter activity has been sequenced in its entirety and found to contain multiple putative regulatory sites. A series of deletion mutants linked to the CAT reporter gene was used to examine functional domains of the 2.2-kilobase sequence. The results suggest that promoter activity is contained in nucleotides -91 to +103 in a GC-rich region of the MRP genome. Promoter activity contained within this sequence, however, is modulated by both positive and negative regulatory elements. Certain of the regulatory sites contain consensus sequences for positive and negative regulatory elements which have been found in the promoter regions of other genes. Primer extension analysis indicates the presence of multiple major transcriptional start sites from the MRP promoter. Sequence analysis of MRP genomic and complementary DNAs has defined the exon/intron boundaries and the organization of a portion of the 5'-end region of the MRP genome. The results of these studies thus provide new insight in site-specific domains which may function in the regulation of MRP gene expression.
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PMID:Cloning and sequence analysis of the promoter region of the MRP gene of HL60 cells isolated for resistance to adriamycin. 804

HL60 cells isolated for resistance to Adriamycin (HL60/ADR) overexpress a 190-kDa ATP binding protein which has a minor sequence homology with P-glycoprotein. It has also been observed that HL60/ADR overexpress the MRP gene which was first identified as a component of a non-P-glycoprotein mediated multidrug resistance of H69/ADR cells [Cole et al., Science (Washington DC), 258: 1650, 1992]. A complementary DNA of MRP has been cloned and based on the deduced sequence encodes a member of the superfamily of proteins which bind ATP and function in various transport processes [Cole et al., Science (Washington DC), 258: 1650, 1992]. In view of this it was of interest to identify the protein encoded by MRP and determine if it may be related to p190. In the present study we have prepared antisera against three synthetic peptides which correspond to the deduced sequence of the MRP protein. Proteins reactive with the antisera have been examined in HL60/ADR cells using Western blot analysis. All antisera react with a 190 kDa protein contained in membranes of resistant but not sensitive cells. One antiserum used for further studies is not reactive with P-glycoprotein contained in membranes of HL60 cells isolated for resistance to vincristine. Analysis of subcellular fractions demonstrates that p190 is present primarily in the endoplasmic reticulum with lower levels also present in plasma membranes. Treatment of HL60/ADR cells with tunicamycin results in the appearance of a 165-kDa resistance associated protein which reacts with the antipeptide serum. The results of this study therefore demonstrate that the MRP gene encodes a 190-kDa membrane bound glycoprotein.
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PMID:The MRP gene associated with a non-P-glycoprotein multidrug resistance encodes a 190-kDa membrane bound glycoprotein. 810 65

MRP, a gene recently isolated from a non-P-glycoprotein-mediated multidrug-resistant small cell lung cancer cell line, is a candidate multidrug-resistance gene. Mitoxantrone, an anthracenedione antitumor agent, frequently selects for non-P-glycoprotein-mediated multidrug resistance in in vitro models. To determine whether mitoxantrone-selected multidrug resistance was due to overexpression of MRP, we examined the expression of MRP in four mitoxantrone-selected, multidrug-resistant human tumor cell lines, using a reverse transcriptase/polymerase chain reaction assay. Results from these experiments suggest that overexpression of MRP does not appear to play a primary role in mitoxantrone-selected multidrug resistance in these cell lines, and that other novel drug-resistance mechanisms are likely.
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PMID:Analysis of MRP mRNA in mitoxantrone-selected, multidrug-resistant human tumor cells. 818 74


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