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)

We examined the levels of expression of the multidrug resistance-associated protein (MRP) gene quantified by Northern blot analysis in comparison with those of the MDR1 gene determined by reverse transcription-polymerase chain reaction (RT-PCR) in 104 non-small-cell lung cancer (NSCLC) specimens [59 adenocarcinoma (Ad), 40 squamous cell carcinoma (Sq), four large cell carcinoma (La) and one adeno-squamous carcinoma (AdSq)]. Thirty-three (31.7%) of the 104 NSCLC expressed the MRP gene at various levels. The NSCLC showing high (++) levels of MRP gene expression (19 out of 33, 57.6%) were predominantly squamous cell carcinomas (Ad, 5; Sq, 13; La, 1) (P < 0.05). Six of the eight NSCLCs expressing high levels of MRP mRNA and no MDR1 (MRP ++, MDR1-) were squamous cell carcinomas. Sixty-one of the 104 NSCLC patients received chemotherapy with MRP-related anti-cancer drugs [vindesine (VDS) and etoposide (VP-16)]. Twenty-three patients (37.7%) with tumour expressing high or moderate levels of MRP showed significantly worse prognoses than those with non- or low-MRP-expressing tumours (P < 0.05). These results suggest that the level of MRP gene expression is related to the histopathology and prognosis of NSCLC.
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PMID:Expression of the multidrug resistance-associated protein (MRP) gene in non-small-cell lung cancer. 766 60

Intrinsic low-level resistance to anti-cancer drugs is a major problem in the treatment of gastrointestinal malignancies. To address the problem presented by intrinsically resistant tumours, we have isolated two monoclonal lines from LoVo human colon adenocarcinoma cells: LoVo/C7, which is intrinsically resistant to doxorubicin (DOX); and LoVo/C5, which shows the same resistance index for DOX as the mixed parental cell population. For comparison, we have included in the study a LoVo-resistant line selected by continuous exposure to DOX and expressing a typical multidrug resistant (MDR) phenotype. In these cell lines we have studied the expression and/or activity of a number of proteins, including P-glycoprotein 170 (P-gp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), glutathione (GSH)-dependent enzymes and protein kinase C (PKC) isoforms, which have been implicated in anti-cancer drug resistance. Intracellular DOX distribution has been assessed by confocal microscopy. The results of the present study indicate that resistance in LoVo/C7 cells cannot be attributed to alterations in P-gp, LRP or GSH/GSH-dependent enzyme levels. Increased expression of MRP, accompanied by alterations in the subcellular distribution of DOX, has been observed in LoVo/C7 cells; changes in PKC isoform pattern have been detected in both intrinsically and pharmacologically resistant cells.
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PMID:Characterization of a clonal human colon adenocarcinoma line intrinsically resistant to doxorubicin. 921 35

Acrolein (AC) and chloroacetaldehyde (CHA) are metabolites of the non-multidrug resistance cytotoxic drugs cyclophosphamide and ifosfamide. It has previously been reported that both metabolites can induce extensive depletion of glutathione (GSH) in vitro and in vivo and that this depletion occurs at drug concentrations in the micromolar range. A link between the function of the multidrug resistance-associated protein (MRP) and the intracellular concentration of GSH has also been demonstrated. To determine whether AC and CHA can modulate the function of MRP by inducing GSH depletion, we used two human lung cancer cell lines overexpressing MRP: the large cell carcinoma cell line COR-L23/R and the adenocarcinoma cell line MOR/R0.4, along with their respective sensitive parental lines, COR-L23/P and MOR/P. We showed that micromolar concentrations of AC and millimolar concentrations of CHA are able to deplete GSH concentrations in the cell lines studied. In addition, concentrations of 50 micrometer AC and 5 mm CHA could completely reverse the daunorubicin (DNR) and vinblastine accumulation deficit present in COR-L23/R and partially reverse the DNR accumulation deficit in MOR/R0.4. In contrast, AC and CHA did not reverse the drug accumulation deficit in the P-glycoprotein-overexpressing lung cancer cell line H69/LX4. The effect of CHA and AC on drug accumulation was related to the GSH depletion, as we found a concentration-dependent relationship between the GSH levels and the reversal of the accumulation deficit for both AC and CHA. To substantiate further this correlation, we increased cellular GSH content in AC- and CHA-treated cells with the GSH ethyl ester. An increase in cellular GSH levels in CHA- and AC-treated COR-L23/R cells was accompanied by a restoration of the DNR accumulation deficit. No significant effect of the GSH ethyl ester was detected on DNR accumulation in COR-L23/P parental cells. In conclusion, treatment with AC or CHA can reverse the drug accumulation deficit of MRP-overexpressing cells, and this effect appears to be mediated by GSH depletion.
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PMID:Modulation by acrolein and chloroacetaldehyde of multidrug resistance mediated by the multidrug resistance-associated protein (MRP). 981 3

Because local recurrence is common after a curative resection for advanced gastric cancer, there has been significant interest in adjuvant chemotherapy. However, the overall effect of chemotherapy remains debatable regarding patients with advanced gastric adenocarcinoma. Multidrug resistance is thought to be a major cause of failure in cancer chemotherapy, and thus the expression of P-glycoprotein (P-Gp), multidrug resistance-associated protein (MRP), and lung-resistance protein (LRP) in tumor cells was evaluated by immunohistochemistry. In 20 gastric adenocarcinomas, 11 (55%), 2 (10%), and 0 (0%) were positive for MRP, LRP, and P-Gp. In malignant lymphomas, only 3 out of 10 cases were positive for MRP (30%). The positive rate of MRP staining was significantly higher in well and moderately differentiated adenocarcinomas (80%) than in poorly differentiated adenocarcinomas (20%). With regard to the degree of MRP expression and histological cell type, higher grades (grade 2-3) were observed only in well and moderately differentiated adenocarcinomas. In terms of the positive-stained cells and staining intensity, heterogeneity was observed in the staining profile of MRP. The proliferative cell nuclear antigen labeling index (PCNA LI) of MRP-positive and MRP-negative cases was 49.3% +/- 11.6% and 49.4 +/- 6.9%, respectively. No correlation was observed between the MRP expression and PCNA LI. In conclusion, the incidence of MRP expression in gastric cancer was the highest in three different multidrug resistance-related epitopes. An evaluation of the MRP expression thus seemed to be beneficial for determining the optimal strategy of chemotherapy.
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PMID:Histopathological assessment of multidrug resistance in gastric cancer: expression of P-glycoprotein, multidrug resistance-associated protein, and lung-resistance protein. 1033 9

Several organic anions are actively extruded from intestinal epithelial cells into the lumen and vascular sides. To examine the role of the multidrug resistance-associated protein (MRP) family in the intestinal efflux of organic anions, the function and expression of these proteins were investigated with Caco-2, a human adenocarcinoma cell line that retains many of the characteristics of normal enterocytes. [(3)H]2,4-Dinitrophenyl-S-glutathione (DNP-SG) and [(3)H]17beta-estradiol 17-beta-D-glucuronide (E(2)17betaG), typical substrates for MRP1 and cMOAT (canalicular multispecific organic anion transporter)/MRP2, were taken up into brush-border membrane vesicles (BBMVs) from Caco-2 in an ATP-dependent manner, with K(m) values of 16.9 +/- 7.2 and 9.4 +/- 1.2 microM, respectively. The uptake of [(3)H]DNP-SG into BBMVs was osmotically sensitive and stimulated to some extent by other nucleotide triphosphates (GTP, CTP, and UTP) but not by ADP or AMP. An ATPase inhibitor, vanadate, inhibited the ATP-dependent uptake of [(3)H]DNP-SG to some extent. Reverse-transcriptase polymerase chain reaction resulted in the amplification of MRP1, MRP3, and MRP5. Northern blot analysis indicated extensive expression of cMOAT/MRP2 and MRP3 and only minimal expression of MRP1 and MRP5. Although cMOAT/MRP2 was continuously expressed throughout the culture period, MRP3 was not expressed immediately after the confluent state was reached. Collectively, the presence of ATP-dependent transport systems for DNP-SG and E(2)17betaG was demonstrated in Caco-2 cells. Because cMOAT/MRP2 and MRP3 may be expressed on brush-border and basolateral membranes in epithelial cells, respectively, the transport activity associated with BBMVs may result from the function of cMOAT/MRP2.
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PMID:Function and expression of multidrug resistance-associated protein family in human colon adenocarcinoma cells (Caco-2). 1060 57

The influence of antibiotics, particularly ofloxacin (OF), a commonly used antimicrobial fluoroquinolone, on the multidrug resistance (MDR) phenotype of the HCT-8 cell line was studied. This cell line was grown in OF containing medium for several months and the expression of the MDR phenotype was followed through the analysis of the expression and functionality of the P-glycoprotein (Pgp), the chemosensitivity to daunorubicin (DNR), and the mRNA expression of mdr-1, multidrug resistance-associated protein (MRP), and topoisomerase IIalpha and IIbeta genes. Replacement of OF by penicillin streptomycin (PS) resulted in a significant decrease in mdr-1 mRNA expression, which was found to correlate with a decrease in the expression and functionality of the Pgp. After antibiotic starvation for 4 weeks, cells grown in antibiotic-free medium were then exposed to PS or OF; these cells showed an increase in mdr-1 mRNA/Pgp and MRP mRNA expression without a decrease in DNR cytotoxicity. OF cultured cells exhibited a significant increase in Pgp expression without evidence of the functionality of the Pgp. An increase in topoisomerase IIalpha mRNA expression was observed with time and with the number of passages of the cell line without any relationship to the presence of antibiotics in the culture medium. These results showed that extensive use of antibiotics, particularly the quinolones, can modify the phenotype of the HCT-8 colon adenocarcinoma cell line.
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PMID:Influence of the fluoroquinolone ofloxacin on the intrinsic expression of multidrug resistance phenotype in HCT-8 human colon carcinoma cells. 1080 41

A 66-year-old female patient underwent left upper lobectomy and dissection of the mediastinal lymph nodes. The pathological diagnosis was well-differentiated papillary adenocarcinoma of the lung with metastasis to the mediastinal lymph nodes, p-T2N2MO, stage IIIA. After the operation, she was treated by chemotherapy including lipophilic anticancer compounds (carboplatin and VP-16). The patient unexpectedly showed long survival for 6 years and 2 months without obvious recurrence or metastasis of the cancer. The anticancer compounds were not effective on the recurrent lesions and then she died due to respiratory failure 8 months after recurrence. The autopsy revealed pleural dissemination and intrapulmonary metastasis. Immunohistochemical analysis showed increased multidrug resistance-associated protein (MRP)-positive tumor cells in the recurrent and metastatic lesions, while few MRP-positive cells were apparent in the primary lesion. The MRP-positive cells were accompanied by p53 nuclear accumulation in the carcinoma. This was a case of pulmonary adenocarcinoma with acquired multidrug resistance caused by MRP overexpression and aberrant p53 after chemotherapy.
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PMID:A case of pulmonary adenocarcinoma with overexpression of multidrug resistance-associated protein and p53 aberration. 1092 27

In the current study, we isolated sublines of the human breast adenocarcinoma cell line MDA 435 that exhibited increasing resistance to epothilone A, a microtubule-stabilizing cytotoxic agent. The resistant cells did not express P glycoprotein or multidrug resistance-associated protein (MRP) which are known mediators of multidrug resistance (MDR). Two groups of epothilone A-resistant cells were selected: cells which exhibited low resistance to both epothilone A and Taxol, and cells which exhibit low resistance to Taxol but high resistance to epothilone A. cDNA microarrays of epothilone A-resistant and Taxol-resistant cells were utilized to further characterize epothilone A resistance. Hierarchical clustering of genes according to their levels of expression indicated that the majority of genes which were highly expressed in epothilone A-resistant cells but not in taxol-resistant MDR cells encode known interferon-inducible proteins. Genes whose expression increased with increasing epothilone A resistance include microtubule-associated GTPases, cytoskeletal proteins, cell signalling proteins and a drug metabolising enzyme. The majority of the genes that were repressed in both epothilone A- and Taxol-resistant cells encode proteins regulating cellular growth signalling mechanisms.
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PMID:Gene expression profiling of epothilone A-resistant cells. 1199 Jul 72

Functional activity of multidrug resistance (MDR) markers (total activity of ABC-transporters, P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP) activities) in human colon adenocarcinoma and normal mucosa was examined. Functional activity of ABC-transporters was revealed in all colon tumors and in 70% of normal mucosa samples investigated. Expression of Pgp and MRP functional activity was determined in about 50% and 70% of colon tumors respectively. Pgp+MRP+ phenotype was determined in 36% of normal mucosa and adenocarcinoma samples. Expression of Pgp+MRP- phenotype was practically the same in normal mucosa and tumors (in 10 and 18% of samples respectively). Pgp-MRP+ phenotype was revealed two times more often in tumors than in mucosa--in 36 and 18% respectively. On the contrary, Pgp-MRP- phenotype was detected more rarely in tumors than in mucosa (in 10 and 36% of samples respectively). Transporters different from Pgp and MRP were also determined in some tumors and normal mucosa. At the patients with expression of Pgp function in normal mucosa the activity of the transporter was revealed in 25% of tumor samples only. On the contrary, at the patients with expression of MRP function in normal mucosa the activity of the transporter was revealed in 70% of tumor samples. At the patients with no expression of Pgp or MRP activity in normal mucosa the function of the transporters in tumors was determined in 60% and 70% of samples respectively. It is concluded that functional activity of various ABC-transporters (Pgp, MRP and other different from Pgp and MRP) is expressed in human colon adenocarcinoma; expression of ABC-transporters functional activity in normal mucosa does not predict MDR phenotype of the tumor.
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PMID:[Functional activity of ABC transporters (markers of multidrug resistance) in human colon adenocarcinoma and normal colonic mucosa]. 1251 89

The purpose of this study is to evaluate the effects of newly synthesized 4-aryl-1,4-dihydropyridine and pyridines on drug efflux mediated by multidrug resistance-associated protein 1 (MRP1, ABCC1). These compounds were designed to maximize inhibition of P-glycoprotein and minimize calcium channel binding activity, based on structure modifications of niguldipine. A [3H]vinblastine accumulation study was conducted in human small cell lung cancer H69AR (overexpressing MRP1) and wild type H69 cells. Five out of 16 dihydropyridines and 6 out of 9 pyridines were found to significantly increase the intracellular accumulation of vinblastine in resistant H69AR cells (p<0.01) at a concentration of 2.5 microM. Daunomycin accumulation studies, determined using a flow cytometric assay, were also performed in H69AR and human pancreatic adenocarcinoma Panc-1 cells and the results were highly correlated with those obtained from the [3H]vinblastine accumulation studies. Four compounds, which significantly increased vinblastine accumulation, were tested for their effect on daunomycin cytotoxicity in H69AR cells and found to significantly decrease the IC50 of daunomycin, confirming the accumulation study results. Compounds were also tested for their effect on intracellular glutathione (GSH) concentrations, a cosubstrate for MRP1-mediated efflux in H69AR and Panc-1 cells. No significant changes in the intracellular GSH level were observed in H69AR cells after treatment with these test compounds. However, following a 2-hr and 24-hr incubation with a dihydropyridine compound, Im, and its pyridine derivative IIm, there was a small (approximately 20%) but statistically significant decrease in intracellular GSH in Panc-1 cells. Our results indicate that some dihydropyridine and pyridine compounds in our series could inhibit MRP1-mediated transport and that GSH modulation plays a minor, if any, role in this effect.
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PMID:Effects of new 4-aryl-1,4-dihydropyridines and 4-arylpyridines on drug efflux mediated by multidrug resistance-associated protein 1. 1613 54


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