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)

Using cyclosporin A (CsA) to inhibit P-glycoprotein (P-gp) function we showed previously that there was a discordance between the ability of acute myeloid leukemic (AML) blast cells to accumulate daunorubicin and P-gp antigen expression (Xie et al, Leukemia 1995; 9:1882-1887). This discordance suggests that a CsA-sensitive drug efflux mechanism distinct from P-gp is expressed in many clinical samples. In the present study using the ATP depleting agents cyanide, azide, or dinitrophenol to inhibit energy dependent transport processes, we observed even larger increases in daunorubicin accumulation than were seen with CsA. Similar patterns were seen in a wide range of P-gp negative human cancer cell lines. Also the observed cyanide effect did not correlate with the expression of mRNA for multidrug resistance-associated protein (MRP), the only other member of the ABC family of membrane transporters that is known to be capable of effluxing daunorubicin. Thse results suggest that daunorubicin accumulation in many cases of AML is modulated by one or more novel energy-dependent processes that are distinct from P-gp or MRP. We speculate that this novel drug transport mechanism(s) may influence the response of AML patients to daunorubicin and other therapeutic agents.
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PMID:A novel energy dependent mechanism reducing daunorubicin accumulation in acute myeloid leukemia. 900 18

In this study, we report the efflux mechanism of calcein, an organic anion, mediated by a multidrug resistance-associated protein (MRP)-like protein in the intestinal mucosal membrane. The transport of calcein from the mucosal to serosal side was decreased dose-dependently and was significantly lower than that of the opposite direction. In addition, its transport was increased in the presence of metabolic inhibitors and probenecid. Furthermore, the efflux of calcein from the intestinal cell membrane, which was preloaded with calcein acetoxymethyl ester, was predominantly observed in the mucosal side rather than in the serosal side. Its efflux to the mucosal side was inhibited by the metabolic inhibitors and probenecid, not by verapamil which is a P-glycoprotein substrate. These results indicated that the transport of calcein and possibly other organic anions across the intestinal membrane may be regulated by the MRP-like protein, but not P-glycoprotein.
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PMID:Calcein is excreted from the intestinal mucosal cell membrane by the active transport system. 901 Apr 86

A group of ATP-binding cassette (ABC) transporters, including the yeast cadmium transporter (YCF1), the mammalian multidrug resistance-associated protein (MRP), the multispecific organic anion transporter and its congener (MOAT and EBCR), as well as the sulfonylurea receptor (SUR), group into a subfamily by sequence comparison. We suggest that these MRP-related proteins are also characterized by a special, common membrane topology pattern. The most studied ABC transporters, the cystic fibrosis transmembrane conductance regulator (CFTR) and the multidrug resistance (MDR) proteins, were shown to contain a tandem repeat of six transmembrane helices, each set followed by an ATP-binding domain. According to the present study, in contrast to various membrane topology predictions proposed for the different MRP-related proteins, they all seem to have a CFTR/MDR-like core structure, and an additional, large, N-terminal hydrophobic region. This latter domain is predicted to contain 4-6 (most probably 5) transmembrane helices, and is occasionally glycosylated on the cell surface. Since all the MRP-related transporters were shown to interact with anionic compounds, the N-terminal membrane-bound domain may have a key role in these interactions.
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PMID:Membrane topology distinguishes a subfamily of the ATP-binding cassette (ABC) transporters. 901 45

Prior studies have shown that, in some human tumour cells, increased expression of the multidrug resistance gene MDR1 can be induced in response to certain stress conditions such as a transient exposure to cytotoxic agents. Little is known about the possibility of increasing the expression of the recently cloned multidrug resistance-associated protein (MRP) in response to a transient exposure to cytotoxic drugs. In order to examine this possibility, we have used sensitive assays (RT-PCR, flow cytometry) and the sensitive large cell lung cancer cell line, COR-L23/P, and the revertant line (COR-L23/Rev), generated by growing the doxorubicin-selected, MRP-overexpressing resistant variant COR-L23/R without drug exposure for 24-28 weeks. COR-L23/Rev overexpresses MRP, but to a lesser extent than COR-L23/R. COR-L23/Rev rapidly recovered similar levels of MRP mRNA, protein expression, resistance and drug accumulation deficit as COR-L23/R after a 48-72 h exposure to cytotoxic concentrations of doxorubicin or vincristine but not cisplatin. The increase in MRP mRNA could only be detected 3 to 4 days after the transient exposure to drugs. However, when the parental line, COR-L23/P, was exposed to equitoxic doses of doxorubicin, vincristine or cisplatin, no increase in the levels of MRP mRNA could be observed at higher doses (5- to 10-fold the IC50) of doxorubicin or vincristine (but not of cisplatin), we detected a transient increase in the levels of MDR1 mRNA immediately after short-term exposure. In conclusion, we have shown that a human revertant lung cancer cell line (COR-L23/Rev) has the ability to recover quickly, similar levels of MRP expression and resistance as COR-L23/R after a transient exposure to the MDR-drugs doxorubicin and vincristine.
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PMID:Rapid recovery of a functional MDR phenotype caused by MRP after a transient exposure to MDR drugs in a revertant human lung cancer cell line. 901 57

MDR1 (P-glycoprotein), multidrug resistance-associated protein (MRP) and lung resistance protein (LRP) are associated with multidrug resistance in various cancer cells. It is known that P-glycoprotein and MRP are also expressed in several normal tissues. However, the exact location of LRP in normal tissues is still unclear. In order to obtain more insight into the physiological role of LRP, its expression in human normal tissues was examined by an immunohistochemical technique, using one monoclonal antibody, LRP-56. Reverse transcriptase-polymerase chain reaction (RT-PCR) was also utilized for several cell lines and fresh-frozen tissues. P-glycoprotein was found to be expressed in the kidney, adrenal, brain vessels, muscle, lung, pancreas, liver, intestine, placenta and testis. MRP was expressed in the kidney, adrenal, lung, pancreas, muscle, intestine, thyroid and prostate, and its distribution mostly overlapped with that of P-glycoprotein. Interestingly, MRP was not expressed in the liver. LRP at 110 kDa was expressed in the kidney, adrenal, heart, lung, muscle, thyroid, prostate, bone marrow and testis. These findings suggest that LRP as well as P-glycoprotein and MRP plays distinct roles in the physiology of various organs.
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PMID:Lung resistance protein (LRP) expression in human normal tissues in comparison with that of MDR1 and MRP. 902 66

To determine the expression of multidrug resistance-associated protein (MRP) gene and its role in gastric and colon cancers, we analyzed 10 gastric and 10 colon non-drug-selected cell lines and a similar number of tissue samples of these cancers. We compared the expression of MRP and mdrl mRNA in cell lines and tissues using reverse-transcriptase polymerase chain reaction. In mdrl-negative cells, the relationship between the level of MRP gene expression and sensitivity to anticancer drugs was examined. The effect of verapamil, an MRP-modulating agent, was also examined in these cells. The expression of MRP gene in gastric cancer cell lines varied from a low to a high level, but mdrl was not detected in any of these cell lines. Colon cancer cell lines expressed low to intermediate levels of MRP gene, and half of the cells co-expressed low to high levels of mdrl. In tissue samples, the expression pattern of the two multidrug resistance (MDR) genes was broadly similar to that described for the cell lines, except that most of the gastric cancer tissue samples did express low levels of mdrl. No significant correlation was observed between the level of MRP gene expression and sensitivity to anticancer drugs in gastric and colon cell lines. However, verapamil significantly increased the sensitivity to etoposide, doxorubicin and vincristine in cells highly expressing MRP gene. Our results indicate that MRP gene may be important in conferring MDR in gastric and colon cancer cells.
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PMID:The multidrug resistance-associated protein gene confers drug resistance in human gastric and colon cancers. 904 62

The multidrug resistance proteins, discovered as membrane transporters producing chemotherapy-resistance in cancer, are functioning as complex cellular defence systems through recognition and energy-dependent removal of a large variety of toxic agents. The multidrug transporters belong to the ATP-binding cassette (ABC) transporters, present both in prokaryotes and eukaryotes and built from a combination of characteristic membrane-spanning helices and cytoplasmic ATP-binding domains. In mammals the MDR1 (P-glycoprotein) extrudes large hydrophobic compounds and provides the basis of the blood-brain and the blood-testis barrier for such molecules. The multidrug resistance-associated protein (MRP) and its homologues have a major role in the cellular export of large organic anions, including e.g. conjugated bile salts and glutathione-conjugates. The substrate recognition, that is the self and non-self discrimination and the ATP-dependent foreign agent extrusion are directly coupled within the structure of these large plasma membrane proteins. Here we suggest that the multidrug transporters are essential parts of our immune-defence system, working as 'cellular antitoxic' mechanisms.
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PMID:The multidrug transporters--proteins of an ancient immune system. 905 81

Three agents, verapamil, cepharanthine, and 2-[4-(diphenylmethyl)-1-piperazinyl]ethyl-5-(trans-4,6-dimethyl-1, 3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-3-py ridinecarboxylate P-oxide (PAK-104P), that reverse drug resistance in P-glycoprotein (P-Gp)-mediated multidrug-resistant cells were examined for their activity to reverse drug resistance in multidrug resistance-associated protein (MRP)-mediated multidrug-resistant C-A120 cells. Agents other than PAK-104P could not reverse the resistance to doxorubicin in C-A120 cells. PAK-104P moderately reversed the doxorubicin resistance. In contrast, PAK-104P almost completely reversed the resistance to vincristine (VCR) in C-A120 cells as well as in KB-8-5 cells, and other agents moderately reversed the VCR resistance in C-A120 cells. PAK-104P at 10 microM enhanced the accumulation of VCR in C-A120 cells to the level of that in KB-3-1 cells without the agent. PAK-104P competitively inhibited the ATP-dependent [3H]leukotriene C4 uptake in membrane vesicles isolated from C-A120 cells. These findings demonstrate that PAK-104P can completely reverse the resistance to VCR in both P-Gp- and MRP-mediated multidrug-resistant cells and that PAK-104P directly interacts with MRP and inhibits the transporting activity of MRP.
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PMID:Reversal of multidrug resistance-associated protein-mediated drug resistance by the pyridine analog PAK-104P. 905 94

We evaluated the expression of MDR1/p-glycoprotein in paediatric tumours using reverse transcriptase polymerase chain reaction (RT-PCR), RNA dot blot analysis, and immunohistochemistry on formalin fixed paraffin-embedded material with JSB-1 and C-219 monoclonal antibodies, and compared these three techniques. The expression of multidrug resistance-associated protein (MRP) gene was examined by RT-PCR assay. We studied MDR1/p-glycoprotein and MRP expression in 13 samples from 10 neuroblastoma patients, 11 samples from 10 nephroblastoma patients, 2 rhabdomyosarcomas, 1 adrenocortical carcinoma and 10 benign tumours or tumour-like lesions. Eleven of 13 neuroblastomas, 7 of 11 nephroblastomas, 2 rhabdomyosarcomas, 1 adrenocortical carcinoma, and 7 of 10 benign tumours or tumour-like lesions showed MDR1 PCR products. By RNA dot blot analysis, MDR1 transcripts were detectable in 11 of 34 specimens. Immunohistochemically, we detected positive reaction products for JSB-1 in 26 of 36 samples. There was a significant correlation between the immunoreactivity for JSB-1 and the expression of MDR1 mRNA expression by RT-PCR (P = 0.0001). However, the presence of p-glycoprotein immunostaining does not correlate with the MDR1 expression shown by RT-PCR in every case. As for MRP mRNA expression, 9 of 13 neuroblastomas and 10 of 11 nephroblastomas revealed PCR products.
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PMID:Expression of MDR1/p-glycoprotein and multidrug resistance-associated protein in childhood solid tumours. 908 12

Annamycin (Ann) is a highly lipophilic anthracycline antibiotic that has been shown to circumvent MDR-1 both in vitro and in vivo. A liposomal formulation of Ann is currently in phase I clinical trials. The multidrug resistance-associated protein (MRP) has been found to be over-expressed in some human leukemias at relapse and to be a poor prognostic factor in neuroblastoma. We studied the in vitro cytotoxicity and the cellular uptake and efflux of Ann and doxorubicin (Dox) in 2 pairs of human cell lines, breast carcinoma MCF7 and small-cell lung cancer UMCC-1, and their MRP-expressing counterparts, MCF-7/VP and UMCC-1/VP. Resistance indexes were 1.1 and 1.4 for Ann vs. 6.9 and 11.6 for Dox. Ann cellular accumulation was 3- to 5-fold higher than that of Dox in both sensitive and resistant cells. No changes in drug efflux between sensitive and resistant cells were observed in the case of Ann, while Dox efflux at 1 hr was 20-25% higher in resistant than in sensitive cells. By confocal microscopy, the subcellular distribution of Ann was identical in sensitive and resistant cells, localizing mostly in the perinuclear structures, while that of Dox was exclusively nuclear in sensitive cells and nuclear and in the cell membrane in resistant cells. There was a good correlation between the extent of DNA breaks induced by each drug in the different cell lines and cytotoxic effect. Our results indicate that Ann may be effective in the treatment of malignancies in which MRP is a relevant mechanism of clinical resistance.
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PMID:Annamycin circumvents resistance mediated by the multidrug resistance-associated protein (MRP) in breast MCF-7 and small-cell lung UMCC-1 cancer cell lines selected for resistance to etoposide. 909 63


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