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)

Treatment of human glioma A172 cells with 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethy-3-nitrosourea (ACNU) for 2 to 4 hr resulted in a 2- to 3-fold increase in steady-state levels of multidrug resistance-associated protein (MRP) and gamma-glutamylcysteine synthetase (gamma-GCS) mRNA. Nuclear run-on assays revealed a less than 0.5-fold increase in transcription rates of these genes under the same treatment conditions, suggesting that posttranscriptional regulation plays an important role for the increased mRNA levels. In the absence of ACNU, rates of MRP and gamma-GCS mRNA degradation were similar in A172 cells as determined by incubating cells with the RNase inhibitor, Actinomycin D. ACNU treatments resulted in increased MRP mRNA stability. Induction of MRP and gamma-GCS mRNA by ACNU apparently did not require de novo protein synthesis as determined by the use of protein synthesis inhibitor cycloheximide (CHX). However, CHX alone could induce accumulation of gamma-GCS mRNA, also by posttranscriptional mechanism. Taken together, these results demonstrate that (i) posttranscriptional regulation is primarily involved in the induction of MRP and gamma-GCS expression by ACNU and CHX in human glioma cells; and (ii) despite the fact that these two genes have been reported to be frequently co-expressed, their responses to the treatments of RNA and protein synthesis inhibitors are not the same.
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PMID:Posttranscriptional regulation of MRP/GS-X pump and gamma-glutamylcysteine synthetase expression by 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea and by cycloheximide in human glioma cells. 934 68

The efficacy of all chemotherapeutic agents is limited by the occurrence of drug resistance. To further understand resistance to topoisomerase (topo) II inhibitors, 50 sublines were isolated as single clones from parental cells by exposure to etoposide or m-AMSA. Subsequently, a population of cells from each sublines was exposed to three-fold higher drug concentrations allowing 16 stable sublines to be established at higher extracellular drug concentration. Quantitative aspects of MRP and C-MOAT were studied by Northern blotting in 66 resistant cell lines. Increased MRP mRNA was observed in 48.5% of resistant cell lines (64.7% of etoposide resistant cells and 31.3% of m-AMSA resistant cell lines). Increased C-MOAT mRNA was also observed in 39.4% of resistant cell lines (41.2% in etoposide resistant cell lines and 37.5% in m-AMSA resistant cell lines). To characterize the function of C-MOAT, cellular accumulation assay for 3H-etoposide was performed in three resistant cell lines which overexpress C-MOAT but do not express MRP. Accumulation of etoposide was reduced in the cell lines. Our findings suggest that increased MRP and O-MOAT mRNA seems to be an important mechanism of resistance to topo II inhibitors.
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PMID:[Expression of ATP binding cassette superfamily (multidrug resistance-1, multidrug resistance-associated protein, human canalicular multispecific organ anion transporter) mRNA in etoposide and m-AMSA resistant cell lines]. 935 Feb 40

Overexpression of a 110-kD protein (lung resistance-related protein [LRP]) may predict a poor response to chemotherapy in patients with acute myeloid leukemia (AML) and ovarian carcinoma. The LRP gene has recently been mapped to chromosome 16, close to the multidrug resistance-associated protein (MRP) gene. Seventy-seven samples from 67 patients with AML were examined for expression of LRP, MRP, and multidrug resistance (MDR1) mRNA using a semiquantitative reverse transcription polymerase chain reaction (RT-PCR) assay. Results were compared with 29 normal samples (11 normal peripheral blood and 18 normal bone marrow). Thirty-three patients with untreated AML were evaluable for response to chemotherapy. Levels of LRP, but not of MRP or MDR1 mRNA, were significantly higher in eight patients who failed to achieve complete remission (CR) compared with 25 patients who achieved CR (p = 0.033). A positive correlation was demonstrated between LRP and MRP (R = 0.368, p = 0.001) and between MRP and MDR1 mRNA levels (R = 0.301, p = 0.01) in the 77 clinical samples analyzed. In AML samples, a significant difference in MDR1 mRNA levels was found between presentation (47 samples) and relapse (30 samples) (p = 0.031). No significant difference was seen in LRP mRNA levels between these two groups or in eight patients studied sequentially at both presentation and relapse. Thirteen samples (10 at presentation, 3 at relapse) were analyzed for LRP protein expression by flow cytometry. Eight (5 at presentation, 3 at relapse) displayed greater than 10% positive cells (range 15-86%). These data suggest that LRP gene overexpression may constitute a novel mechanism of multidrug resistance.
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PMID:Expression of the human major vault protein LRP in acute myeloid leukemia. 935 65

Transduction of hematopoietic progenitors with a multidrug resistance gene like mdr-1 or mrp aims to protect bone marrow from toxicity of chemotherapeutic agents. The interest in the use of mrp as an alternative to mdr-1 gene transfer for bone marrow protection lies in its different modulation. Indeed, classical P-gp reversal agents, tested in the clinic to decrease mdr-1 tumor resistance, have little or no effect on MRP function. This would allow, in the same patient, the use of reversal agents to decrease P-gp tumor resistance without reversing bone marrow protection of the transduced hematopoietic cells provided by multidrug resistance-associated protein (MRP). As a first step, we have constructed and tested two different mrp-containing vectors with either the Harvey retroviral long terminal repeat (LTR) or PGK as promoters and generated ecotropic producer cells. We have shown by Southern blot analysis that retroviral supernatant from these producer cells can efficiently transmit the mrp gene to target cells. Mrp expression could be detected by fluorescence-activated cell sorting (FACS) analysis in the producer cells. The transduced cells have increased resistance to doxorubicin, vincristine, and etoposide. Furthermore, chemoprotection of the transduced cells was increased after selection with chemotherapeutic agents in the presence of glutathione, a co-factor for MRP function. These data indicate that mrp retroviral vectors may be useful for chemoprotection and selection.
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PMID:Retrovirus-mediated gene transfer of the multidrug resistance-associated protein (MRP) cDNA protects cells from chemotherapeutic agents. 935 24

Methoxymorpholino doxorubicin (MMRDX) is an anthracycline analogue that is able to overcome tumor cell resistance to classical anthracyclines. Mechanisms for increased MMRDX cytotoxicity were analyzed in a small cell lung carcinoma cell line (GLC4), its 300-fold doxorubicin-resistant and multidrug resistance-associated protein (MRP)-over-expressing subline (GLC4/ADR), an ovarian carcinoma cell line (A2780) and its 100-fold doxorubicin resistant and P-glycoprotein (P-gp)-overexpressing subline A2780AD. Cross-resistance, measured with the MTT assay at MMRDX concentration resulting in 50% growth inhibition, was 1.8-fold in GLC4/ADR and 4.5-fold in A2780AD compared to their respective parental cell lines. Cellular MMRDX accumulation was equal in GLC4 and GLC4/ADR and 2-fold lower in A2780AD compared to A2780. Doxorubicin fluorescence was analyzed with confocal laser scan microscopy. Fluorescence was nuclear in sensitive, and cytoplasmic in resistant, cell lines, while MMRDX fluorescence was found in the nucleus in all cell lines. Pre-incubation with the MRP blocker MK 571 restored in GLC4/ADR cells the nuclear doxorubicin fluorescence pattern, as observed in GLC4 cells. MMRDX, thus, can largely overcome cross-resistance in these P-gp- and MRP-overexpressing doxorubicin-resistant cell lines. Our results suggest that MMRDX is not a substrate for MRP-mediated resistance.
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PMID:Mechanisms for high methoxymorpholino doxorubicin cytotoxicity in doxorubicin-resistant tumor cell lines. 935 83

The multidrug resistance-associated protein (MRP) mediates the cellular excretion of many drugs, glutathione S-conjugates (GS-X) of lipophilic xenobiotics and endogenous cysteinyl leukotrienes. Increased MRP levels in tumor cells can cause multidrug resistance (MDR) by decreasing the intracellular drug concentration. The physiological role or roles of MRP remain ill-defined, however. We have generated MRP-deficient mice by using embryonic stem cell technology. Mice homozygous for the mrp mutant allele, mrp-/-, are viable and fertile, but their response to an inflammatory stimulus is impaired. We attribute this defect to a decreased secretion of leukotriene C4 (LTC4) from leukotriene-synthesizing cells. Moreover, the mrp-/- mice are hypersensitive to the anticancer drug etoposide. The phenotype of mrp-/- mice is consistent with a role for MRP as the main LTC4-exporter in leukotriene-synthesizing cells, and as an important drug exporter in drug-sensitive cells. Our results suggest that this ubiquitous GS-X pump is dispensable in mice, making treatment of MDR with MRP-specific reversal agents potentially feasible.
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PMID:Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein. 935 5

Multidrug resistance (MDR) in human cancer cells is multifactorial. Previously, we reported on the association between expression of P-glycoprotein (Pgp), the multidrug resistance-associated protein (MRP), and the lung resistance protein (LRP) with the MDR phenotype in the NCI panel of 60 human cancer cell lines used for in vitro anticancer drug screening. Eight cell lines from this panel, manifesting widely divergent levels of in vitro drug resistance were chosen to investigate the role of MRP and LRP expression at the molecular level. LRP mRNA levels, as determined by ribonuclease protection assay, varied significantly among the 8 cell lines, and correlated closely with in vitro drug resistance to both MDR and non-MDR related drugs. LRP mRNA expression was determined to be a stronger correlate of drug sensitivity than protein expression. In contrast, MRP mRNA levels were not significantly correlated with drug sensitivity. The rates of newly transcribed LRP or MRP mRNA did not correlate with mRNA levels, indicating that mRNA stability or other features of processing may be important in regulation of LRP and MRP mRNA levels. Using Southern blot analysis, LRP gene amplification was shown not to be associated with LRP overexpression. These data suggest that LRP expression may be an important determinant of the MDR phenotype in cell lines intrinsically resistant to cancer chemotherapeutic agents.
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PMID:Increased LRP mRNA expression is associated with the MDR phenotype in intrinsically resistant human cancer cell lines. 937 36

Treatment of human glioma A172 cells with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), an alkylating antitumor agent the primary target of which has been thought to be DNA, resulted in elevated expression of mRNA for multidrug resistance-associated protein (MRP) within the first 2 h and then a decrease in expression 24 h after the treatment. Western blot analyses revealed that levels of MRP in these ACNU-treated cells paralleled mRNA levels. Membrane vesicles prepared from ACNU-treated cells also displayed elevated transport activities for leukotriene C4, a known substrate for MRP. Gamma-glutamylcysteine synthetase (gamma-GCS) mRNA expression was coinduced with MRP by ACNU. Because gamma-GCS is the rate-limiting enzyme involved in the de novo biosynthesis of glutathione, increases in glutathione were also transiently induced by ACNU. These results demonstrate for the first time that the expression of functional MRP and gamma-GCS can be transiently coinduced by ACNU. Multiple short exposures (1 h) of ACNU following a long duration (1 week) of drug-free conditions resulted in the development of an ACNU-resistant population (designated A172R) that overexpressed MRP/gamma-GCS mRNA and had elevated transport activities for leukotriene C4. A172R exhibited cross-resistance to the antitumor drug doxorubicin and heavy metal sodium arsenate but not to cisplatin. Our results also demonstrate that intermittent treatments of human glioma cells with ACNU can lead to the development of MRP-related multidrug resistance. These results, taken together, reveal a possible new mechanism of the development of drug resistance for the antitumor nitrosoureas.
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PMID:Transient induction of the MRP/GS-X pump and gamma-glutamylcysteine synthetase by 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea in human glioma cells. 939 52

In contrast to intrinsic drug resistance, induced multidrug resistance in gastric cancer cells has not been well studied. Therefore, two doxorubicin-resistant cell lines, (SNU-1DOX, SNU-16DOX), were derived in vitro from gastric carcinoma cell lines (SNU-1, SNU-16) respectively, and their characteristics were investigated. These resistances were not associated with overexpression of mdrl, multidrug resistance associated protein 1 (MRP1), pi or liver class of glutathione S transferase (GST pi, GSTL), heat shock protein 70 (HSP70), p53 or transglutaminase C (TGC). Levels of p21WAF1 RNA and topoisomerase II protein were decreased in the SNU-16DOX, but not in SNU-1DOX. However, the subsequent enzyme activity of topoisomerase II in SNU-16DOX was not decreased, but rather increased in SNU-16DOX. Furthermore, both resistant cell lines showed lower uptake and higher efflux of doxorubicin and induced cross-resistance to etoposide and vincristine in addition to doxorubicin, indicating a multi-drug resistance phenotype. In summary, we report two gastric carcinoma cell lines exhibiting induced multidrug resistance phenotype and suggest that mdrl, MRP1, GST, TGC, HSP70 and p53 do not play important roles in induced drug resistance in these cell lines. The role of changes in topoisomerase II activity and/or protein is still inconclusive, and p21WAF1 is associated with induced multidrug resistance in the SNU-16DOX gastric carcinoma cell line.
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PMID:Characteristics of human gastric carcinoma cell lines with induced multidrug resistance. 941 98

Resistance of tumor cells to chemotherapeutic drugs can not only be caused by treatment with antineoplastic agents but also by radiotherapy. The aim of this study was to analyze whether ionizing radiation can influence the mRNA expression of proteins which have been found to be involved in drug resistance of tumor cells. Human tumor cell lines (MCF-7, LXF and Sk-Mel) were treated with single doses of irradiation (5, 10 and 20 Gy). The expression of the resistance related proteins glutathione S-transferase-pi (GST-pi), topoisomerase II alpha (Topo II), thymidylate synthase (TS), O6-methylguanine-DNA-methyltransferase (MGMT), P-glycoprotein (Pgp), glutathione peroxidase (GPX) multidrug resistance-associated protein (MRP) and also of the heat-shock protein 70 (HSP 70) were determined at the mRNA level during the time interval from 1.5 to 72 h post-irradiation and compared with their corresponding controls. We also examined whether a relationship exists between these proteins and the proliferative activity (histone 3, Ki-67, statin) of the cells. We found that exposure of MCF-7, LXF and Sk-Mel cells to ionizing radiation increases the expression of the mRNA of GST-pi. Topo II, TS, HSP 70 and proliferation markers were also altered by exposure to ionizing radiation, but there was no common response of the three cell lines. No significant changes were observed in the expression of MGMT, Pgp, GPX and MRP after radiation treatment. Drug resistance tests revealed that irradiated MCF 7 cells were less sensitive to doxorubicin than non-irradiated control cells. Our results indicate that ionizing irradiation modifies the expression of some proteins involved in drug resistance and the response of MCF 7 cells to doxorubicin and may, therefore, play a role in clinical drug response.
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PMID:Messenger RNA expression of resistance factors in human tumor cell lines after single exposure to radiation. 941 87


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