Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A cell line (GZL-8) was established by cloning from ascitic fluid of an untreated ovarian carcinoma patient. The cells grew rapidly, accumulated lipids and showed chromosomal alterations. One of the marker chromosomes showed characteristics of a Y-like chromosome. This unusual finding was confirmed by DNA hybridisation using specific probes to the Y chromosome. The cells stained with fluorescent antibodies to desmoplakin and cytokeratins 8, 18, 19, and weakly with vimentin but not with desmin. The presence of epithelial membrane antigen, human milk fat globulin, alpha-lactalbumin, alpha-fetoprotein, placental alkaline phosphatase and oestrogen receptor-related antigen was demonstrated by indirect immunoperoxidase staining, but no CA-125 antigen could be detected. The cells showed positive reaction with antibodies to P-glycoprotein. The function of the P-glycoprotein transport system was demonstrated by the rhodamine-123 release test. The cells were initially responsive to doxorubicin, and to high concentrations of cisplatin. Growth inhibition by doxorubicin, especially at low doses was enhanced by the addition of verapamil or tamoxifen. This was shown by the soft agar clonogenic assay, by direct cell counting and by the MTT reducing test. Our results show that combination between drug and sensitivity modulators may be of potential clinical value in ovarian cancer.
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PMID:A cell line with unusual characteristics from an ovarian carcinoma patient: modulation of sensitivity to antitumour drugs. 134 52

An immortalized brain capillary endothelial cell line displaying blood-brain barrier characteristics may represent a useful tool for studying blood-brain barrier endothelial cell differentiation and for the in vitro prediction of drug brain penetration. In the present study, we have established a rat cerebral capillary endothelial cell line (CR3) by genomic introduction of the immortalizing SV40 large T gene under the control of the human vimentin promoter. The CR3 cell line displayed endothelial morphological and biochemical characteristics for up to 30 passages. However, the CR3 cell line did not spontaneously express the specific blood-brain barrier markers gamma-glutamyl transpeptidase and mdr P-glycoprotein. However, when the cells were treated with the cell differentiating agent all-trans-retinoic acid, the blood-brain barrier markers were induced. Retinoic acid-treated CR3 cells may thus represent a useful tool for biological and pharmacological research related to the blood-brain barrier.
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PMID:Induction of blood-brain barrier differentiation in a rat brain-derived endothelial cell line. 766 32

Acquired resistance to chemotherapeutic drugs by tumor cells is an important obstacle to effective therapy of human malignancy. These resistance cell lines originated from human or rodent have been characterized by increased expression of MDR (Multidrug-resistance) gene and P-glycoprotein which plays as efflux pump of drugs from cells. These multidrug-resistance sublines also have been reported increased activities of protein kinases and glutathione S-transferase-pi. Although there have been extensive biophysical and biochemical characterization of the differences between parental lines and MDR tumor cell sublines, morphologic observations have been limited. In this study, filamentous cytoskeletons which involve many biological phenomena such as maintenance of cell morphology, mitosis, cellular movement, transport, and adhesion, were observed by confocal laser microscopy. To compare the expression of each cytoskeletons, fluorescent intensities of cells stained for each cytoskeletons were measured by confocal laser microscopic system. Utilizing this methodology, higher microtubular expression was observed in HL-60/ADR and K562/ADR than in their parental lines, but no significant differences of actin and vimentin were observed. Phosphorylation by protein kinases has been established as a key factor in the regulation of cytoskeletal function. But little is known about the role of protein phosphorylation in cytoskeletal function. Since increased activities of PKC and PTK were detected in HL-60/ADR, the effect of PKC inhibitor, staurosporine (STR), or PTK inhibitor, genistein (GNS), on cell growth was detected. STR and GNS reduced the resistance to Adriamycin in HL-60/ADR. Furthermore, STR and GNS disrupted the filamentous structure of microtubules in HL-60/ADR, and suppressed the expression of microtubules to 37%, and 49%, respectively. In contrast, PKC activator, phorbol ester (TPA), caused stronger microtubular assembling in HL-60/ADR, and increased the expression of microtubules to 134%. Resulting from this study, it is likely that acquired MDR of HL-60 and K562 was associated with increased expression of microtubules, and microtubular assembling or disassembling was considered to be regulated in part by PKC and PTK.
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PMID:[Features of filamentous cytoskeletons in acquired multidrug-resistance of HL-60 human leukemia cell line]. 790 88

The emergence of drug-resistant tumor cells remains a major problem in cancer chemotherapy. Resistance to multiple unrelated antineoplastic drugs may be related, in part, to expression of the P-glycoprotein. The cell line RD, derived from an embryonic rhabdomyosarcoma tumor, was used as an in vitro model to examine the development of drug resistance. A cell line resistant to actinomycin D (RD-DAC) was developed by growing RD in increasing concentrations of the drug. The ID50 (concentration of drug needed to induce a 50% reduction in cell growth) of the resultant line to actinomycin D was more than 15 times that of the parental line. The resistant line was cross-resistant to vincristine and doxorubicin. Resistance to actinomycin D resulted in increased P-glycoprotein expression, which was associated with a change in desmin and vimentin expression. These results suggest that exposure to chemotherapeutic drugs can induce not only classical multidrug resistance, but also a process of cellular differentiation in rhabdomyosarcoma cells.
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PMID:Actinomycin D causes multidrug resistance and differentiation in a human rhabdomyosarcoma cell line. 791 94

Cryptophycin is a cytotoxic dioxadiazacyclohexadecenetetrone isolated from cyanobacteria of the genus Nostoc. Incubation of L1210 leukemia cells with cryptophycin resulted in dose-dependent inhibition of cell proliferation in parallel with increases in the percentage of cells in mitosis (half-maximal effects at < 10 pM). Indirect immunofluorescence studies demonstrated that treatment of A-10 vascular smooth muscle cells with cryptophycin results in marked depletion of cellular microtubules and reorganization of vimentin intermediate filaments, similar to the effects of vinblastine. Cytochalasin B caused the depolymerization of microfilaments in these cells, while neither vinblastine nor cryptophycin affected this cytoskeletal component. Pretreatment of cells with taxol prevented microtubule depolymerization in response to either vinblastine or cryptophycin. While microtubule depolymerization in response to vinblastine was rapidly reversed by removal of the drug, cells treated with cryptophycin remained microtubule depleted for at least 24 h after removal of the compound. Combinational treatments with vinblastine and cryptophycin resulted in additive cytotoxicity. Ovarian carcinoma and breast carcinoma cells which are multiply drug resistant due to overexpression of P-glycoprotein are markedly less resistant to cryptophycin than they are to vinblastine, colchicine, and taxol. Therefore, cryptophycin is a new antimicrotubule compound which appears to be a poorer substrate for P-glycoprotein than are the Vinca alkaloids. This property may confer an advantage to cryptophycin in the chemotherapy of drug-resistant tumors.
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PMID:Cryptophycin: a new antimicrotubule agent active against drug-resistant cells. 791 8

The mouse mdr2 P-glycoprotein (P-gp) and its human MDR3 homologue are present in high concentrations in the canalicular membrane of hepatocytes. Mice lacking this protein are unable to secrete phosphatidylcholine (PC) into bile, suggesting that this P-gp is a PC translocator. We have tested this in fibroblasts from transgenic mice expressing the MDR3 gene under a vimentin promoter. Transgenic and control fibroblasts were incubated with [14C]choline to label PC. When the labeled cells were incubated with a PC transfer protein and acceptor liposomes, transfer of radioactive PC was enhanced in transgenic cells relative to the wild type controls. We conclude that the MDR3 P-glycoprotein is able to promote the transfer of PC from the inner to the outer leaflet of the plasma membrane, supporting the idea that this protein functions as a PC flippase.
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PMID:The human MDR3 P-glycoprotein promotes translocation of phosphatidylcholine through the plasma membrane of fibroblasts from transgenic mice. 795 36

1. Morphine-6-glucuronide is one of the major metabolites of morphine. The potent analgesic action of this compound together with its potential lower apparent toxicity in man, when compared with morphine, indicated its clinical importance. 2. Primary cultures of porcine brain capillary endothelial cells were used to study brain penetration of morphine-6-glucuronide. Biochemical characterization of the cell cultures revealed a marked enrichment in enzymatic activity of alkaline phosphatase (56 fold) and angiotensin converting enzyme (230 fold) as compared to whole brain tissue. By immunostaining the presence of vimentin, factor VIII, the tight junction associated protein ZO-1, and P-glycoprotein was shown. Functional characterization revealed that the carrier system responsible for transport of neutral amino acids was intact. 3. Uptake and transport of morphine-6-glucuronide was marginal and in the range of the extracellular marker sucrose. However, uptake of morphine-6-glucuronide was enhanced significantly (P < 0.0001) in presence of the inhibitors of P-glycoprotein, verapamil or vincristine. The finding that morphine-6-glucuronide may serve as a substrate for P-glycoprotein was confirmed in multidrug-resistant P388 tumour cells. 4. We conclude that penetration of the blood-brain barrier by morphine-6-glucuronide may depend on the expression of the product of the multidrug-resistance (MDR) gene in brain capillary endothelial cells.
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PMID:Evidence for P-glycoprotein-modulated penetration of morphine-6-glucuronide into brain capillary endothelium. 886 18

The 2 clones, LoVo 5 and LoVo 7, derived from untreated LoVo WT human colon adenocarcinoma cells and exhibiting different sensitivity to doxorubicin (DOX), were compared in order to identify possible determinants of intrinsic drug resistance. A multidrug resistant variant cell line, selected from LoVo WT cells by continuous exposure to DOX (LoVo DX), was also included in the study. Analysis of the expression and organization of cytoskeletal elements by flow cytometry and fluorescence microscopy evidenced a positive correlation between vimentin expression and DOX resistance in LoVo 7 and LoVo DX cells, whereas differences in actin, tubulin or cytokeratin did not seem to relate to drug response. The expression and localization of different drug transporters commonly implicated in drug resistance, i.e., the MDR1 gene product P-glycoprotein (P-gp), the multidrug resistance-related protein MRP and the lung resistance-related protein LRP were also investigated by means of flow cytometry and fluorescence microscopy, following labeling with specific monoclonal antibodies. Surface expression of P-gp was only detected in LoVo DX cells, which also exhibited increased MRP and LRP protein levels. However, significant amounts of P-gp were found at intracellular sites in the intrinsically resistant LoVo 7 clone. Modulation of P-gp function by cyclosporin A was found to alter DOX accumulation and efflux in LoVo 7 cells, indicating that intracellular P-gp plays a functional role in drug trafficking and suggesting possible implications in determining the intrinsic resistance displayed by this clone.
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PMID:Intracellular P-glycoprotein expression is associated with the intrinsic multidrug resistance phenotype in human colon adenocarcinoma cells. 1092 53

Anaplastic thyroid carcinoma is a rapidly growing, aggressive neoplasm affecting the elderly which does not respond to most of the therapies. We established cultured cell lines from four untreated tumors. The cultures grew in a monolayer of spindle-shaped cells in three cell lines and of small polygonal cells in one line, having relatively long doubling times and chromosomal abnormalities. The xenotransplantation of the lines in athymic nude mice produced tumors with a histology similar to the original tumors. The immunocytochemical staining showed the expression of PCNA, HLA-class 1, cytokeratin, vimentin and FAS (fatty acid synthase) but not CEA, desmin or P-glycoprotein. The lines secreted TPA, IL-6, IL-8 and few or no thyroid-related hormones in the culture supernatant. One cell line produced G-CSF. The chemosensitivity assay revealed intrinsic drug resistance to nine out of 11 antineoplastic agents. The reverse transcriptase-polymerase chain reaction (RT-PCR) detected MRP (multidrug resistance-associated protein) mRNA but not mdr (multidrug resistance protein)-1 and mdr-3 mRNAs. This finding indicates that the multidrug resistance of these lines is mediated by a P-glycoprotein-unrelated mechanism. The RT-PCR also presented FAS mRNA in all the lines, and IL-6 and IL-8 mRNAs in some of the lines.
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PMID:Biological characteristics and chemosensitivity profile of four human anaplastic thyroid carcinoma cell lines. 1168 81

The phenomenon of multidrug resistance (MDR) in human cancers is the major cause of failure of chemotherapy. To better understand the molecular events associated with the development of different types of MDR, a classical MDR P-glycoprotein expressing gastric carcinoma cell line and an atypical MDR P-glycoprotein-negative variant were analyzed by cDNA array hybridization. Of 588 cDNAs spotted on the array, a total of 9 genes showed differences in mRNA expressions. An enhanced expression level of 3 genes could be detected in both different MDR models (HLH, IR21, CCT5, Tx P-1), 4 genes were overexpressed solely in classical MDR cells (Hsp27, Rcl, aldehyde dehydrogenase 1, vimentin), whereas the expression of one gene was increased in atypical MDR cells (ProTa). Furthermore, the mRNA expressions of 3 genes were down-regulated in atypical MDR cells (Hsp27, vimentin, JNK2), whereas a decrease in mRNA expression in classical MDR cells could be determined for none of them. These differences were confirmed by a semiquantitative RT-PCR approach. Further characterization of these factors may provide more insight into the biology and development of different types of MDR in human gastric carcinomas. Moreover, these genes may be potential candidate factors for the diagnostics and/or prognosis of clinical drug resistance.
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PMID:Identification of differentially expressed genes in classical and atypical multidrug-resistant gastric carcinoma cells. 1253 67


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