Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P33527 (ABCC1)
 1,164 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the incidence is very low, the prognosis of anaplastic carcinoma of the thyroid is very poor regardless of the results of various therapeutic trials. We found that the mechanism of anti-cancer drug resistance in anaplastic carcinoma of the thyroid was not explicable only in terms of expression of the mdr1 and its gene product, P-glycoprotein. Therefore, expression of multidrug resistance-associated protein (MRP) mRNA was examined in 11 anaplastic thyroid carcinomas and eight anaplastic thyroid carcinoma cell lines. High MRP mRNA expression was recognized in 7/11 and 8/8, respectively. Our results may contribute to elucidation of the mechanism of anti-cancer drug resistance in this neoplasm.
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PMID:Expression of multidrug resistance-associated protein (MRP) in anaplastic carcinoma of the thyroid. 805 90

Amplification of the gene encoding multidrug resistance-associated protein (MRP) and overexpression of its cognate mRNA have been detected in multidrug-resistant cell lines derived from several different tumor types. To establish whether or not the increase in MRP is responsible for drug resistance in these cell lines, we have transfected HeLa cells with MRP expression vectors. The transfectants display an increase in resistance to doxorubicin that is proportional to the levels of a M(r) 190,000, integral membrane protein recognized by anti-MRP antibodies. The transfectants are also resistant to vincristine and VP-16 but not to cisplatin. The results demonstrate that MRP overexpression confers a multidrug resistance phenotype similar to that formerly associated exclusively with elevated levels of P-glycoprotein.
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PMID:Overexpression of multidrug resistance-associated protein (MRP) increases resistance to natural product drugs. 827 68

Two doxorubicin-selected human tumor cell lines, H69AR and HT1080/DR4, display a multidrug resistance phenotype but do not overexpress P-glycoprotein. Recently, a 6.5-kilobase mRNA encoding a novel member of the ATP-binding cassette superfamily of transport proteins, designated multidrug resistance-associated protein (MRP), has been identified in the H69AR cell line. In the present study, the levels of MRP mRNA were found to be 14-fold higher in HT1080/DR4 cells relative to sensitive HT1080 cells. Southern blotting indicates that gene amplification contributes to the overexpression of MRP in HT1080/DR4 cells. Using a 4-kilobase MRP complementary DNA probe, MRP genes were localized to 2-5 chromosomes bearing homogeneously staining regions and to multiple double minute chromosomes in H69AR cells. Resistant H69AR cells also contained a new der(16) with a structural aberration affecting 16p13.1, the normal cellular locus of the MRP gene. The MRP probe hybridized to two small homogeneously staining regions (hsr) in HT1080/DR4 cells including hsr(7)(p12p15). MRP localization was restricted to the normal cellular locus, 16p13.1, in the parental H69 and HT1080 cells and the drug-sensitive H69PR revertant cells. Our data provide combined evidence that amplification of the MRP gene is associated with the expression of drug resistance in selected solid tumor cell lines.
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PMID:Localization of a novel multidrug resistance-associated gene in the HT1080/DR4 and H69AR human tumor cell lines. 839 19

We studied the transport mechanism of pirarubicin (THP) in HL60 and its THP-resistant (HL60/THP) cells, which showed no expression of mdr1 mRNA on Northern blot analysis. Under physiological conditions, the uptake of THP by both types of cell was time- and temperature-dependent. The amount of drug transport in the resistant cells was significantly less than that in the parent cells within 3 min of incubation. THP uptake was significantly higher in the presence than in the absence of 4 mM 2,4-dinitrophenol (DNP) in glucose-free Hanks' balanced salt solution in both HL60 and HL60/THP cells and the increases were approximately equal. In the presence of DNP, the uptake of THP by both types of cell was concentration-dependent, and there were no significant differences in the apparent kinetic constants (Michaelis constant (Km), maximum velocity (Vmax) and Vmax/Km) for THP uptake between HL60 and HL60/THP cells. Additionally, THP transport was competitively inhibited by its analogue doxorubicin. The efflux of THP from HL60/THP cells was significantly greater than that from HL60 cells, and the release from both types of cell was completely inhibited by decreasing the incubation temperature to 0 degrees C and by treatment with DNP in glucose-free medium. In contrast, the P-glycoprotein inhibitors verapamil and cyclosporin A did not inhibit THP efflux. However, genistein, which is a specific inhibitor of multidrug resistance-associated protein (MRP), increased the THP remaining in the resistant cells, and the value was approximately equal to that of the control group in the sensitive cells. These results suggest that THP is taken up into HL60 and HL60/THP cells via a common carrier by facilitated diffusion, and then pumped out in an energy-dependent manner. Furthermore, the accelerated efflux of THP by a specific mechanism, probably involving MRP, other than the expression of P-glycoprotein, resulted in decreased drug accumulation in the resistant cells, and was responsible, at least in part, for the development of resistance in HL60/THP cells.
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PMID:Transport mechanism of anthracycline derivatives in human leukemia cell lines: uptake and efflux of pirarubicin in HL60 and pirarubicin-resistant HL60 cells. 854 74

A specific and quantitative reverse-transcription polymerase chain reaction (RT-PCR) assay was developed for measuring the mRNA of the multidrug resistance-associated protein (MRP). A region corresponding to bp 3897-4471 of MRP cDNA is amplified, which encompasses approximately half of the second nucleotide-binding domain (NBD2). In two multidrug resistant (MDR) sublines of the HL-60 human acute myeloid leukemia (AML) cell line which overexpress MRP but not P-glycoprotein, the assay detects elevated levels of MRP mRNA (4- to 8-fold) relative to the drug-sensitive parental cells (designated HL-60/W). Blast cells from 24 patients with AML were also studied for MRP expression using this RT-PCR method. Expression of MRP was normalized for that of beta-actin in the blast cells, which was also determined by RT-PCR. All of these blast cell samples had MRP expression that was detectable after 35 PCR cycles. Eighteen of these patients samples had levels of expression of MRP mRNA equal to or less than that expressed by HL-60/W cells. In six patient blast cell specimens, the expression of MRP mRNA was up to 1.7-fold higher than that of HL-60/W cells. In 21 specimens, the steady-state intracellular accumulation of daunorubicin (1 microgram/ml, 3h) was also determined. The blast cells with MRP mRNA expression higher than HL-60/W had a lower median accumulation of daunorubicin compared to those whose MRP expression was less than HL-60/W, suggesting a functional defect in drug transport in the cells with higher MRP expression; a similar trend toward lower daunorubicin accumulation was also noted in the one-third of samples that displayed the highest expression of MDR1 mRNA (also determined by RT-PCR). These studies illustrate the range of expression of MRP in AML blast cell specimens. The identification of MRP overexpression in MDR AML cell lines and in some AML patient blast cells with low intracellular daunorubicin accumulation warrants further study of MRP as a component of clinical drug resistance in AML.
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PMID:Expression of multidrug resistance-associated protein (MRP) mRNA in blast cells from acute myeloid leukemia (AML) patients. 855 37

A human bladder cancer cell line resistant to adriamycin (ADM), T24/ADM9 has been established in vitro by exposing T24 parent cells to progressively higher concentrations of the drug over a period of 12 months. The T24/ADM9 cells were found to be 9 times more resistant to ADM than the T24 parent, and showed various degrees of cross-resistance to an ADM derivative, vinea alkaloids and a DNA topoisomerase II (Topo II)-targeting agent, etoposide. No significant differences was observed in the cellular accumulation of ADM between the T24/ADM9 and T24 parent cells. A Northern blot analysis showed an overexpression of multidrug resistance-associated protein (MRP) mRNA, but no overexpression of multidrug resistance-1 (MDR1) mRNA was observed in the T24/ADM9 cells. A flow cytometric analysis showed that the MDR1 gene product, P-glycoprotein (Pgp), is not expressed on the T24/ADM9 cells. T24/ADM9 showed approximately the parental level of DNA Topo II catalytic activity. In Western blot and Northern blot analyses, however, the cellular level of DNA topo II was apparently much lower in T24/ADM9 than in the T24 parent. Thus, these results suggest that a decreased cellular level of DNA Topo II and an overexpression of MRP gene may be responsible for the expression of an MDR phenotype in the T24/ADM9 cells and that such non-Pgp-mediated, atypical MDR may develop in bladder cancer treated with chemotherapy including ADM.
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PMID:Non-P-glycoprotein-mediated atypical multidrug resistance in a human bladder cancer cell line. 856 4

The efficacy of taxol against a wide range of sensitive and refractory solid tumors has prompted extensive investigation into the factors that influence its cytotoxicity. Our preliminary observations indicated that taxol had a superior antitumor effect against human cells (Daudi, K562, 2008, 2008/C13*, 2780 and C70) compared with its effect against rodent cells (WS, WR, NIH3T3, and CHO). Although verapamil, an inhibitor of P-glycoprotein function, markedly increased the efficacy of taxol against the rodent cells (WS, WR, and CHO), the expression of P-glycoprotein was found only at low levels in the WR cells. In addition, levels of the multidrug resistance-associated protein (MRP), as assessed by reverse transcriptase-polymerase chain reaction analysis, were found to be higher in the human than in the rodent cells, although MRP mRNA was not detected by northern blotting. Transport studies indicated that the reduced sensitivity of the rodent cells to taxol was due to decreased intracellular taxol levels and reduced intracellular binding. However, no correlation was found between the intracellular binding of taxol and the intracellular levels of alpha- and beta-tubulin, or the intracellular concentration of polymerized tubulin. These studies were extended further by assessing the binding of taxol to semi-purified microtubule proteins from WS, CHO and 2008/C13* cells in vitro. The microtubule protein preparations from WS, CHO and 2008/C13* cells, which have a 50-fold difference in their sensitivity to taxol, were found to bind equal amounts of radiolabeled taxol, and this binding was inhibited (80%) in the presence of unlabeled taxol. These results lead us to propose the presence in the rodent cells of an alternative taxol transport system that is distinct from the P-glycoprotein and MRP systems.
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PMID:Species-specific differences in taxol transport and cytotoxicity against human and rodent tumor cells. Evidence for an alternate transport system. 857 97

The human pancreatic tumour cell line PSN1/ADR, stepwise selected in 17-510 nM doxorubicin, displayed a multidrug resistance not conferred by P-glycoprotein (P-gp). Resistance to 17-51 nM doxorubicin was accompanied by overexpression of the vesicular marker lung resistance-related protein (LRP). Further selection in 170 nM doxorubicin led to the activation of multidrug resistance-associated protein (MRP) and to the development of drug accumulation/retention defects sensitive to verapamil. In addition, these defects were reversible by the vesicular traffic inhibitors brefeldin A, fluoroaluminate and nocodazole. In contrast, in human ovarian H134AD cells that are resistant to 1700 nM doxorubicin and used as P-gp-positive controls, the drug efflux was inhibited only by verapamil. The tyrosine kinase inhibitor genistein was a potent blocker of doxorubicin efflux in the PSN1/ADR cells but showed no activity in the H134 AD cells. The doxorubicin cytotoxicity in the PSN1/ADR cells was enhanced both by verapamil and brefeldin A, whereas in the parental PSN1 cells they demonstrated the opposite effects, being respectively sensitising and protecting. The P-gp-negative PSN1/ADR cells adapted to 510 nM doxorubicin retained brefeldin A-sensitive doxorubicin accumulation defects while MRP declined. The persistence of brefeldin A-responsive phenotype on the background of variable MRP expression suggests this agent as a useful functional probe for non-P-gp-mediated resistance to plasma-achievable doxorubicin concentrations.
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PMID:Low-level doxorubicin resistance in P-glycoprotein-negative human pancreatic tumour PSN1/ADR cells implicates a brefeldin A-sensitive mechanism of drug extrusion. 860 92

For investigation of relative differences in mRNA expression levels and of correlations in the expression of genes possibly involved in multidrug resistance (MDR) of acute myelogenous leukemias (AML), a complementary DNA polymerase chain reaction (cDNA-PCR) analysis was established for the genes encoding MDR1/P-glycoprotein, the multidrug resistance-associated protein (MRP), topoisomerase II alpha, topoisomerase II beta, topoisomerase I, glutathione S-transferase pi, protein kinase C (PKC) isozymes alpha, beta 1, beta 2, epsilon, eta, theta and cyclin A. In a first descriptive study comprising samples of childhood or adult AML we calculated the mean values from primary (n=14) or relapsed (n=23) states of the diseases, respectively. We found in the latter significant increases of MDR1, MRP, gst pi, and PKC theta gene expression. MDR1 and MRP gene expression levels were generally correlated (rs= +0.4128, P<0.02, n=37), as well as topoisomerase II alpha and cyclin A gene expression levels (rs= +0.8727, P<0.0001, n=35). Within the group of relapsed state AML a significant negative correlation between the gene expression levels of MDR1 and topoisomerase II alpha (rs= -0.5500, P<0.01, n=22) was observed. Remarkably, highly significant positive correlations were found for MDR1/PKC eta (rs= +0.5560, P<0.001, n=32), MRP/PKC theta (rs= +0.6573, P<0.0001, n=34) and MRP/PKC eta (rs= +0.5241, P<0.005, n=32).
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PMID:Expression of PKC isozyme and MDR-associated genes in primary and relapsed state AML. 864 57

Cells exposed to calcein acetoxymethyl ester (calcein AM) in the growth medium become fluorescent following cleavage of calcein AM by cellular esterases to produce the fluorescent derivative calcein. It has previously been shown by others that multidrug resistant cells which overexpress P-glycoprotein accumulate much less fluorescent calcein than the corresponding parental cells. We have now examined the transport of calcein in multidrug resistant cells which overexpress an alternative transporter, the multidrug resistance-associated protein (MRP). Accumulation of calcein fluorescence was greatly reduced in the MRP-overexpressing human lung cancer cell lines COR-L23/R and MOR/R compared with their parental lines. Energy depletion resulted in a considerably increased accumulation in the resistant lines. Treatment of resistant cells with buthionine sulfoximine (BSO), which depletes cellular glutathione (GSH), did not affect calcein accumulation, in marked contrast to our previous results for daunorubicin or the fluorescent probe rhodamine 123. Genistein, verapamil, cyclosporin A and ouabain were also each able to modify, to some extent, accumulation of daunorubicin, whilst having essentially no effect on calcein accumulation. However, the organic anion transport inhibitor probenecid was able to increase accumulation of both calcein and daunorubicin in the resistant cells. Genistein and verapamil treatment preferentially reduced the GSH content of resistant cells, whilst probenecid did not. However, probenecid caused a clear decrease in release of GSH from resistant cells into the medium.
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PMID:On the relationship between the probenecid-sensitive transport of daunorubicin or calcein and the glutathione status of cells overexpressing the multidrug resistance-associated protein (MRP). 884 45


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