Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human U-1285 and GLC(4) cell lines, both derived from small cell carcinoma of the lung, are present in doxorubicin-sensitive (U-1285 and GLC(4)) and doxorubicin-resistant MRP-expressing (U-1285dox and GLC(4)/ADR) variants. These sublines were examined here with respect to their susceptibilities to the toxic effects of selenite and compared to the toxic effects of selenite on the promyelocytic leukemia cell line HL-60 and its doxorubicin-resistant P-glycoprotein expressing variant. The drug-resistant U-1285dox and GLC(4)/ADR sublines proved to be 3- and 4-fold, respectively, more sensitive to the cytotoxicity of selenite than the drug-sensitive U-1285 and GLC(4) sublines, whereas no difference was observed between the HL-60 sublines. The presence of doxorubicin at a concentration equal to the IC(10) did not significantly potentiate the toxic effects of selenite. The presence of selenite did not significantly affect the expression of the multi-drug resistant proteins (MRP1, LRP and topoisomerase IIalpha) in the drug-resistant cells. The activities of thioredoxin reductase (TrxR) were higher (50 and 25%, respectively) in the drug resistant cell sublines U-1285dox and GLC(4)/ADR compared to the drug-sensitive parental lines. The activity of glutathione reductase (GR) was essentially the same in the drug-sensitive and -resistant cell lines. Exposure to selenite resulted in a 4-fold increase in both TrxR and GR activities in U-1285 cells, an effect, which was less pronounced in the presence of doxorubicin. Under similar conditions the increase in the TrxR activity in the resistant U-1285dox cell line, was only 30% and the activity of GR was unaltered. Different responses in the activity of the key enzymes in selenium metabolism are one possible mechanism explaining the differential cytotoxicity of selenium in these cells.
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PMID:Drug-resistant human lung cancer cells are more sensitive to selenium cytotoxicity. Effects on thioredoxin reductase and glutathione reductase. 1203 72

Drug resistance, one of the major obstacle in the successful anticancer therapy, can be observed at the outset of therapy (intrinsic resistance) or after exposure to the antitumor agent (acquired resistance). To gain a better insight into the mechanisms of intrinsic resistance we have analyzed two human cell types derived from untreated tumors: MCF-7 breast cancer and A549 non small cell lung cancer (NSCLC). We have examined: the cytotoxic effect induced by doxorubicin (DOX); the time course of drug accumulation by flow cytometry and intracellular drug distribution by confocal microscopy; the expression and distribution of proteins related to anthracycline resistance, such as P-gp (P-glycoprotein), MRP1 (multidrug resistance-associated protein) and LRP (lung resistance-related protein). The cytotoxicity assays showed that A549 cells were less sensitive than MCF-7 cells to the DOX treatment in agreement with the different DOX uptake. Moreover, while in A549 cells DOX was mostly located in well defined intracytoplasmic vesicles, in MCF-7 cells it was mainly revealed inside the nuclei. The analysis of P-gp and MRP expression did not show significant differences between the two cell lines while a high expression of LRP was detected at the nuclear envelope and cytoplasmic levels in A549 cells. These findings suggest that the lower sensitivity to DOX treatment showed by lung carcinoma cells could be ascribed to drug sequestration by LRP inside the cytoplasmic compartments.
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PMID:Role of the lung resistance-related protein (LRP) in the drug sensitivity of cultured tumor cells. 1211 Feb 77

Mean nuclear area has been consistently shown by different researchers to be a strong and independent prognostic factor in advanced ovarian carcinoma. However, the biological background of the prognostic value of nuclear area remains unclear. Others have found that the multidrug-resistance (MDR) related protein LRP has strong prognostic value. In the present study we have analysed whether the mean nuclear area and LRP are related in tumour tissue of the ovary obtained at the debulking operation before the administration of chemotherapy in 40 patients. The mitotic activity index, volume percentage epithelium, standard deviation of nuclear area and the other MDR-related proteins P-glycoprotein (JSB-1, MRK-16) and MRP have been investigated additionally for correlations and prognostic value. No correlations were found between the morphometrical features and MDR-related proteins. Mean nuclear area tended to be larger in LRP positive tumours, but the correlation was not significant. In multivariate analysis LRP-protein expression and mean nuclear area had independent prognostic value. Further studies are required to elucidate the biological background of the strong prognostic value of mean nuclear area in advanced ovarian cancer.
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PMID:Expression of multidrug resistance-associated markers, their relation to quantitative pathologic tumour characteristics and prognosis in advanced ovarian cancer. 1212 80

Chronic myeloid leukemia blast phase (CML-BP) cells commonly express the multidrug transporter, P-glycoprotein (Pgp). To determine whether Pgp inhibition improves treatment outcome in CML-BP, the Southwest Oncology Group performed a randomized, controlled trial testing the benefit of the Pgp modulator, cyclosporin A (CsA). Seventy-three eligible patients were assigned to treatment with cytarabine and infusional daunorubicin with or without intravenous CsA. Treatment with CsA yielded no improvement in treatment outcome as measured by the frequency of induction resistance (68% vs 53%), rate of complete remission or restored chronic phase (CR/CP, 8% vs 30%), and survival (3 vs 5 months). Blast expression of Pgp (63%) and LRP (71%) was common, whereas only Pgp adversely impacted the rate of CR/CP (P =.025). We conclude that Pgp has prognostic relevance in CML-BP but that the modulation of Pgp function with CsA as applied in this trial is ineffective.
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PMID:Cyclosporine inhibition of P-glycoprotein in chronic myeloid leukemia blast phase. 1217 16

The purpose of this study was to determine the incidence of three genes associated with multidrug resistance (MDR) in multiple myeloma in relation to treatment status. MDR1/Pgp (P-glycoprotein) expression was detected in 41% of 93 myeloma samples. Generally, the incidence of MDR1/Pgp expression was higher in pretreated samples, and treatments with doxorubicin and/or vincristine were more effective in MDR1/Pgp expression than with alkylating agents. A significant association was observed between MDR1 /Pgp-positiveness and the ability of verapmil to increase doxorubicin sensitivity, suggesting functional relevance of MDR1/Pgp expression. MRP (multidrug resistance protein) expression was detected in 20.5% of 88 myeloma samples, in 26% at the mRNA level analyzed by quantitative reverse transriptase-polymerase chain reaction, and in only 3 of 79 samples by immunohistochemistry. LRP (lung-resistance protein) protein expression was observed in 12.5% of 72 myeloma samples. MRP and LRP expression was similar in samples with and without prior therapy. Approximately 80% of the myeloma samples with detectable mRNA expression of MDRI and MRP exhibited low expression levels corresponding to < 10% of the Pgp- and MRP-overexpressing multidrug-resistant human myeloma cell lines 8226/Dox6 and 8226/DOXint40c, respectively. Some normal bone marrow samples showed higher levels of MRP mRNA as compared to myeloma specimens, whereas MDRI mRNA expression in normal bone marrow was much lower (< or = 5%) than that in 8226/Dox6. These findings indicate a requirement to develop single-cell assays for MRP detection in multiple myeloma that are more sensitive than immunohistochemistry and might be useful to evaluate the incidence of genes associated with MDR.
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PMID:Expression of MDR1/P-glycoprotein, the multidrug resistance protein MRP, and the lung-resistance protein LRP in multiple myeloma. 1218 Apr 85

This study was undertaken to investigate the expression and predictive value for outcome of multidrug resistance-associated (MDR) proteins P-glycoprotein (Pgp), MRP1, BCRP, and LRP, in advanced testicular germ-cell tumours (TGCT). Paraffin-embedded sections from 56 previously untreated patients with metastatic TGCT were immunostained for Pgp, MRP1, BCRP, and LRP. All patients received platinum-based chemotherapy after orchidectomy. Immunostaining was related to clinicopathological parameters, response to chemotherapy, and outcome. Strong and intermediate expressions of the different MDR-related proteins were: 27 and 41% (Pgp), 54 and 37% (MRP1), 86 and 7% (BCRP), and 14 and 29% (LRP). P-glycoprotein and MRP1 associated, respectively, to low AFP (P=0.026) and high LDH levels (P=0.014), whereas LRP expression associated with high beta-hCG levels (P=0.003) and stage IV tumours (P=0.029). No correlation was found between Pgp, MRP1, and BCRP expression and response to chemotherapy and survival. In contrast, patients with LRP-positive tumours (strong or intermediate expression) had shorter progression-free (P=0.0006) and overall survival (P=0.0116) than LRP-negative patients, even after individual log-rank adjustments by statistically associated variables. Our data suggest that a positive LRP immunostaining at the time of diagnosis in metastatic TGCT is associated with an adverse clinical outcome.
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PMID:Lung resistance-related protein as a predictor of clinical outcome in advanced testicular germ-cell tumours. 1264 25

Intrinsic or acquired drug resistance poses a major challenge to the success of chemotherapy in the clinical management of human cancers. While acquired multidrug resistance (MDR), whereby cells become refractory to multiple drugs, has been extensively investigated, the mechanistic basis for intrinsic resistance remains elusive, so that this condition is largely unmanageable in the clinical setting. To address this issue, we have assessed the effects of the anticancer agent doxorubicin (DX) on a panel of human tumor cell lines originally derived from untreated patients and tried to establish a correlation between cell response and a number of parameters, including drug accumulation and/or drug efflux; differences in expression and/or subcellular distribution of proteins involved in the apoptotic process (e.g., p53, Bcl-2, Bax) and intracellular signal transducers (PKCalpha); changes in key detoxification processes. Based on our results, 'classic' multispecific drug transporters (P-glycoprotein, MDR-related proteins) only seem to play a minor role in the intrinsically resistant phenotype, whereas LRP may contribute to resistance in non-small cell lung carcinoma (NSCLC) cells. No relationship was observed between drug response and expression and/or subcellular localization of apoptosis-related proteins; however, increased PKCalpha levels are associated with poor drug response, suggesting that one or more substrates of this enzyme may be relevant to the resistant phenotype. Finally, overactive glutathione-recycling pathways may contribute to DX resistance.
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PMID:Molecular determinants of intrinsic resistance to doxorubicin in human cancer cell lines. 1268 72

Infants with acute lymphoblastic leukemia (ALL) are more resistant to chemotherapeutic drugs than older children with ALL, except for Ara-C. Drug resistance mechanisms in infant ALL, however, remain unknown. Possibly, multidrug resistance (MDR) proteins like P-glycoprotein, MDR-associated protein (MRP1), lung resistance-related protein (LRP/MVP) and the breast cancer resistance protein (BCRP) play a role. Accordingly, we measured the mRNA levels of these proteins in infants (n=13) and non-infants (n=13) with ALL, using quantitative RT-PCR. Infants expressed 2.4-fold less BCRP mRNA (P=0.009) than non-infants with ALL. MDR1, MRP1 and LRP/MVP expression did not differ between both groups. MDR gene expression levels did not correlate to prednisolone, vincristine, daunorubicin or Ara-C cytotoxicity, except for BCRP expression, which correlated with resistance to Ara-C (Rs=0.53, P=0.012), suggesting that Ara-C might be a BCRP substrate. However, culturing patients ALL cells in the presence of the BCRP inhibitor Ko143 had no effect on Ara-C sensitivity. Inhibiting Bcrp1 in the Mdr1a-, Mdr1b- and Mrp1-deficient and Bcrp1-overexpressing mouse cell line Mef3.8/T6400, also did not modulate Ara-C cytotoxicity. Therefore, we conclude that Ara-C is not a substrate for BCRP and that MDR proteins do not play a significant role in drug resistance in infant ALL.
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PMID:Multidrug resistance genes in infant acute lymphoblastic leukemia: Ara-C is not a substrate for the breast cancer resistance protein. 1457 27

The resistance of tumors to classic taxanes (paclitaxel and docetaxel) presents problems in chemotherapy. Thus, new taxanes with higher antitumor activity in resistant tumors are synthesized. This study compared cytotoxicity and transport of paclitaxel and docetaxel with novel taxanes SB-T-1103, SB-T-1214, and SB-T-1216 in adriamycin-sensitive (MDA-MB-435) and -resistant (NCI/ADR-RES) human breast cancer cells. The cell lines examined differ in adriamycin transport, suggesting different expression of ABC membrane transporters. Reverse transcription-polymerase chain reaction revealed that NCI/ADR-RES cells expressed high levels of P-glycoprotein mRNA, which was absent in MDA-MB-435 cells, while the opposite was true for MRP2 mRNA. Both cell lines shared or differently expressed eight other ABC transporters and LRP. NCI/ADR-RES cells were 1,000-fold more resistant to paclitaxel and 600-fold more resistant to docetaxel in MTT assay than MDA-MB-435 cells, but almost equally sensitive to SB-T-1103, SB-T-1214, and SB-T-1216. This complied with the fact that NCI/ADR-RES cells absorbed almost 20-fold less [14C]paclitaxel, about 7-fold less docetaxel, and almost equal amounts of SB-T-1103, SB-T-1214, and SB-T-1216 as the MDA-MB-435 cells. Verapamil increased uptake of [14C]paclitaxel by NCI/ADR-RES cells 7-fold and decreased its efflux 2.5-fold; in contrast, it weakly influenced uptake and increased the efflux in MDA-MB-435 cells. SB-T-1103 and SB-T-1216 did not influence transport of paclitaxel, but SB-T-1214 decreased [14C]paclitaxel uptake in both cell lines indicating inhibition of uptake. This suggests that the novel taxanes are not inhibitors of P-glycoprotein. However, novel taxanes exert much higher activity on resistant tumor cells than classic taxanes and seem to be potential drugs for therapy in taxane-resistant tumors.
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PMID:Transport and cytotoxicity of paclitaxel, docetaxel, and novel taxanes in human breast cancer cells. 1605 35

The aim of this work was to determine the expression of the multidrug resistance (MDR) proteins, namely MDR1 (P-glycoprotein), MRP1 (multidrug resistance-related protein) and LRP (lung resistance-related protein), in 87 samples of breast carcinoma. Detection of these proteins was provided by using indirect enzymatic immunohistochemistry. Our findings were compared with the other clinical and pathological parameters: expression of Her2/neu, estrogen receptor status (ER), progesteron receptor status (PR), histological grade and regional lymph node status. For statistical analysis, non-parametric two sided Mann-Whitney-U test was used. Majority of breast carcinoma specimens show positivity for these proteins. The MDR1 and MRP1 signal was found in the cytoplasm of cancer cells. The expression of LRP was detected in the cytoplasm close to the nuclear membrane. The samples were positive for MDR1 protein in 57%, for MRP1 in 84% and for LRP in 79%. Comparing our results with other clinical and pathological parameters, negative correlation between ER, PR and MDR1 expressions and histological grading status was found. No associations were observed between the MRP1 and LRP proteins and histological grading, as well as between the expression of three MDR proteins and the other clinically relevant parameters. In conclusion, high frequency of expression of MDR proteins in breast carcinoma cells suggests, that these proteins might be an important factor of drug resistance in breast carcinoma. Nevertheless, the negative correlation between the histological grade of malignancy of tumor and the expression of ER, PR and MDR1 indicates possible influence of progressive tumor cell de-differentiation. However, this finding has to be confirmed in additional evaluations.
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PMID:Expression of MDR proteins in breast cancer and its correlation with some clinical and pathological parameters. 1657 68


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