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 have analysed the contribution of several parameters, e.g. drug accumulation, MDR1 P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and topoisomerase (topo) II, to drug resistance in a large set of drug-resistant variants of the human non-small-cell lung cancer cell line SW-1573 derived by selection with low concentrations of doxorubicin or vincristine. Selection with either drug nearly always resulted in MDR clones. The resistance of these clones could be explained by reduced drug accumulation and was associated with a decrease rather than an increase in the low MDR1 mRNA level. To test whether a decrease in MDR1 mRNA indirectly affected resistance in these cells, we introduced a MDR1-specific hammerhead ribozyme into wild-type SW-1573 cells. Although this led to a substantial reduction in MDR1 mRNA, it did not result in resistance. In all resistant clones we found an altered form of the multidrug resistance-associated protein (MRP), migrating slightly slower during SDS-polyacrylamide gel electrophoresis than MRP in parental cells. This altered MRP was also present in non-P-gp MDR somatic cell hybrids of the SW-1573 cells, demonstrating a clear linkage with the MDR phenotype. Treatment of crude cellular membrane fractions with N-glycanase, endoglycosidase H or neuraminidase showed that the altered migration of MRP on SDS-PAGE is due to a post-translational modification. There was no detectable difference in sialic acid content. In most but not all doxorubicin-selected clones, this MDR phenotype was accompanied by a reduction in topo II alpha mRNA level. No reduction was found in the clones selected with vincristine. We conclude from these results that selection of the SW-1573 cell line for low levels of doxorubicin or vincristine resistance, predominantly results in MDR with reduced drug accumulation associated with the presence of an altered MRP protein. This mechanism can be accompanied by other resistance mechanisms, such as reduced topo II alpha mRNA in case of doxorubicin selection.
Br J Cancer 1995 Aug
PMID:Altered MRP is associated with multidrug resistance and reduced drug accumulation in human SW-1573 cells. 764 Feb 9

It was found that the mechanism of anti-cancer drug resistance in anaplastic carcinoma of the thyroid was not explicable only in terms of expression of mdr1 and its gene product, P-glycoprotein. The multidrug resistance-associated protein (MRP), another member of the mdr gene family, may be involved in anti-cancer drug resistance of this carcinoma. The MRP expression was examined immunohistochemically in 8 cell lines and 73 thyroid cancer tissues; its frequency in anaplastic carcinoma (52%) was significantly higher than that in other thyroid cancer types.
Cancer Lett 1995 Aug 16
PMID:Expression of multidrug resistance-associated protein (MRP) in thyroid cancers. 765 21

We have characterised an etoposide-resistant subline of the small-cell lung cancer cell line, UMCC-1, derived at our centre. Subline UMCC-1/VP was developed by culturing the parent line in increasing concentrations of etoposide over 16 months. UMCC-1/VP is 20-fold resistant to etoposide by MTT assays, relative to the parent line, and is cross-resistant to doxorubicin, vincristine and actinomycin D, but not to taxol, cisplatin, melphalan, thiotepa or idarubicin. Topoisomerase II immunoblotting demonstrates a 50% reduction of the protein in the resistant subline. The UMCC-1/VP subline demonstrates a marked decrease in the accumulation of [3H]etoposide relative to the parent line, as well as a modest reduction in the accumulation of daunorubicin. Reverse transcription-polymerase chain reaction assays demonstrate no detectable mdr1 expression but marked expression of the multidrug resistance-associated protein (MRP) gene in the resistant subline. Northern blotting with an MRP cDNA probe confirms marked overexpression of the MRP gene only in the UMCC-1/VP subline. Western blotting with antisera against MRP peptide confirms a 195 kDa protein band in the UMCC-1/VP subline. Southern blotting experiments demonstrate a 10-fold amplification of the MRP gene in the resistant subline. Depletion of glutathione with buthionine sulphoximine sensitised UMCC-1/VP cells to daunorubicin and etoposide. Our studies indicate that MRP gene expression may be induced by etoposide and may lead to reduced accumulation of the drug.
Br J Cancer 1995 Sep
PMID:An etoposide-resistant lung cancer subline overexpresses the multidrug resistance-associated protein. 766 58

Multidrug resistance (MDR) in tumour cells is often caused by the overexpression of the plasma membrane drug transporter P-glycoprotein (P-gp) or the recently discovered multidrug resistance-associated protein (MRP). In this study we investigated the specificity and sensitivity of the fluorescent probes rhodamine 123 (R123), daunorubicin (DNR) and calcein acetoxymethyl ester (calcein-AM) in order to detect the function of the drug transporters P-gp and MRP, using flow cytometry. The effects of modulators on the accumulation and retention of these probes were compared in several pairs of sensitive and P-gp- as well as MRP-overexpressing cell lines. R123, in combination with the modulator PSC833, provided the most sensitive test for detecting P-gp-mediated resistance. Moreover, in a 60 min drug accumulation assay R123 can be regarded as a P-gp-specific probe, since R123 is not very efficiently effluxed by MRP. In contrast to R123, a 60 min DNR or calcein-AM accumulation test could be used to detect MRP-mediated resistance. The MRP-specific modulator genistein could be used in combination with DNR, but not with calcein-AM. Vincristine (VCR) can be used to increase the cellular uptake of calcein-AM in MDR cells, but is not specific for MRP. Thus, although the combination of DNR with genistein appeared to be as sensitive as the combination of calcein-AM with VCR, the former may be used to probe specific MRP activity whereas the latter provides a combined (P-gp + MRP) functional MDR parameter. With these functional assays the role and relative importance of P-gp and MRP can be studied in, for example, haematological malignancies.
Br J Cancer 1995 Sep
PMID:Functional detection of MDR1/P170 and MRP/P190-mediated multidrug resistance in tumour cells by flow cytometry. 766 59

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.
Br J Cancer 1995 Sep
PMID:Expression of the multidrug resistance-associated protein (MRP) gene in non-small-cell lung cancer. 766 60

The acquisition of the multidrug resistance phenotype in human tumours is associated with an overexpression of the 170 kDa P-glycoprotein encoded by the multidrug resistance 1 (MDR1) gene, and also with a 190 kDa membrane ATP-binding protein encoded by a multidrug resistance-associated protein (MRP) gene. Human bladder cancer is a highly malignant neoplasm which is refractory to anti-cancer chemotherapy. In order to understand the mechanism underlying multidrug resistance in bladder cancer, we established three doxorubicin-resistant cell lines, T24/ADM-1, T24/ADM-2 and KK47/ADM, and one vincristine-resistant cell line, T24/VCR, from human bladder cancer T24 and KK47 cells respectively. Both T24/ADM-1 and T24/ADM-2 cells which had elevated MRP mRNA levels showed both a cross-resistance to etoposide and a decreased intracellular accumulation of etoposide. T24/VCR cells which had elevated levels of MDR1 mRNA and P-glycoprotein but not of MRP mRNA, showed cross-resistance to doxorubicin. On the other hand, KK47/ADM cells, which had elevated levels of both MRP and MDR1 mRNA and a decreased level of topoisomerase II mRNA, were found to be cross-resistant to etoposide, vincristine and a camptothecin derivative, CPT-11. Our present study demonstrates a concomitant induction of increased levels of MRP mRNA, decreased levels of topoisomerase II mRNA and decreased drug accumulation during development of multidrug resistance in human bladder cancer cells. The enhanced expression of the MRP gene is herein discussed in a possible correlation with the decreased expression of the topoisomerase II gene.
Br J Cancer 1995 May
PMID:Expression of multidrug resistance-associated protein (MRP), MDR1 and DNA topoisomerase II in human multidrug-resistant bladder cancer cell lines. 773 14

The expression of the multidrug resistance-associated protein (MRP), a new glycoprotein involved in drug resistance, was investigated in tumour samples from 80 patients with chronic B-cell malignancies by a quantitative RNase protection assay. In B-cell chronic lymphocytic leukaemia (B-CLL) (n = 32), either treated (n = 18) or untreated (n = 14), a high percentage of patients (20/32: 63%) had relatively high expression levels of the MRP gene (25U or more). In addition, hyperexpression of the MRP gene was demonstrated in 4/10 (40%) untreated patients with B-cell prolymphocytic leukaemia (B-PLL). In contrast, low MRP mRNA expression levels were detected in hairy cell leukaemia (n = 7), non-Hodgkin's lymphoma (n = 13) and multiple myeloma (n = 18). Statistical analysis of MRP expression in untreated CLL (mean +/- SD 29.2 +/- 18.5 U) versus treated CLL (mean +/- SD 26.7 +/- 13.7 U) did not show significant differences in MRP expression between the two groups. Southern blot analysis did not reveal amplification of the MRP gene in the leukaemia samples with elevated MRP mRNA levels. We conclude that B-PLL and B-CLL frequently display high MRP expression and that this hyperexpression is probably due to transcriptional activation and/or increased mRNA stability.
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PMID:High expression of the multidrug resistance-associated protein (MRP) in chronic and prolymphocytic leukaemia. 780 81

Overexpression of multidrug resistance-associated protein (MRP) has been detected in resistant cell lines derived from a variety of tumor types. The deduced amino acid sequence of MRP suggests that it is a member of the ATP-binding cassette transmembrane transporter superfamily that may be glycosylated and/or phosphorylated [S. P. C. Cole et al., Science Washington, DC), 258: 1650-1654, 1992]. Recently, transfection of HeLa cells with MRP expression vectors has demonstrated that the protein is capable of increasing resistance to natural product drugs such as anthracyclines, Vinca alkaloids, and epipodophyllotoxins (C. E. Grant et al., Cancer Res., 54: 357-361, 1994). Although the resistance phenotype of the transfectants is similar to that of the human small cell lung cancer cell line, H69AR, from which MRP was originally cloned, the transfectants differ in their drug accumulation characteristics, relative resistance to certain drugs, and MRP mRNA:protein ratio. Such differences have also been observed among drug-selected cell lines that overexpress MRP, and the underlying causes of these variable phenotypes are presently not known. We have utilized polyclonal anti-MRP-peptide antibodies to compare MRP post-translational modification, stability, processing, and subcellular distribution in the HeLa transfectants and in the drug-selected H69AR cells. These studies establish that MRP in both the transfected and selected cells is an ATP-binding, integral membrane glycophosphoprotein with an apparent molecular weight of 190,000. No obvious differences were detected in the extent or type of glycosylation or the kinetics of processing and turnover of the protein that might contribute to the different characteristics of the transfected and drug-selected cells. Analyses of the subcellular distribution of MRP by isopyknic density gradient centrifugation revealed that approximately 80% of MRP in the HeLa transfectants was associated with a low density plasma membrane fraction while the comparable fraction in the drug-selected H69AR cells contained only approximately 50% of the protein. The remaining MRP and plasma membrane markers were codistributed in higher density fractions consistent with the presence of MRP in endocytotic vesicles. The relatively high proportion of MRP associated with these fractions in H69AR cells may contribute to the lack of an observable accumulation defect in these cells when compared with the transfectants.
Cancer Res 1995 Jan 01
PMID:Characterization of the M(r) 190,000 multidrug resistance protein (MRP) in drug-selected and transfected human tumor cell. 780 19

The multidrug resistance-associated protein (MRP) is a 180- to 195-kDa glycoprotein associated with multidrug resistance of human tumor cells. MRP is mainly located in the plasma membrane and it confers resistance by exporting natural product drugs out of the cell. Here we demonstrate that overexpression of the MRP gene in human cancer cells increases the ATP-dependent glutathione S-conjugate carrier activity in plasma membrane vesicles isolated from these cells. The glutathione S-conjugate export carrier is known to mediate excretion of bivalent anionic conjugates from mammalian cells and is thought to play a role in the elimination of conjugated xenobiotics. Our results suggest that MRP can cause multidrug resistance by promoting the export of drug modification products from cells and they shed light on the reported link between drug resistance and cellular glutathione and glutathione S-transferase levels.
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PMID:Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport. 780 67

We have generated rat and murine monoclonal antibodies against multidrug resistance-associated protein (MRP), a M(r) 180,000-195,000 membrane glycoprotein involved in a non-P-glycoprotein multidrug resistance of human tumor cells. The antibodies were raised against two different segments of MRP and found to be suitable for protein blot analyses, immunohistochemical and cytochemical studies, as well as flow cytometry of permeabilized cells. The antibodies do not cross-react with the human P-glycoproteins. Immunocytochemistry using MRP-overexpressing tumor cells of different histogenetic origins showed that MRP is predominantly located in the plasma membrane. Immunoelectron microscopy confirmed the plasma membrane location of MRP. The MRP antibodies provide a sensitive and specific tool for studies on MRP-mediated multidrug resistance.
Cancer Res 1994 Sep 01
PMID:Immunochemical detection of the multidrug resistance-associated protein MRP in human multidrug-resistant tumor cells by monoclonal antibodies. 791 28


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