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

P-glycoprotein (P-gly), which is responsible for the phenotypic expression of multidrug resistance in cancerous tissue was stained immunohistochemically in previously untreated alpha-fetoprotein (AFP)-producing (n = 20) and nonproducing gastric cancers (n = 20). P-gly, AFP, and carcinoembryonic antigen(CEA) were stained in formalin-fixed paraffin-embedded tissue sections immunohistochemically using the monoclonal antibody JSB-1, anti-AFP, and anti-CEA, respectively. DNA ploidy pattern was determined by Fluorescence Activated Cell Sorter (FACS) analyzer. P-gly was significantly overexpressed in AFP producing gastric cancers (60%) than in AFP nonproducing ones (20%) (P < 0.01). When the result of P-gly staining was analyzed among the AFP-positive cases, P-gly positivity did not emerge either as a significant prognostic factor or as a predictor of the metastatic potentiality of the tumor. The intrinsic overexpression of P-gly in AFP producing gastric cancers proves its biological and morphological similarities to hepatocellular carcinoma. The significantly (P < 0.05) higher incidence of P-gly in diploid tumors indicate that expression of this phenotype might be related to the differentiation of the tumor. P-gly was overexpressed in AFP producing gastric carcinoma and the existing drug resistance, frequent recurrence, and poor prognosis might be explained by presence of P-gly in this carcinoma.
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PMID:Overexpression of P-glycoprotein in untreated AFP-producing gastric carcinoma. 754 56

The goal of our study was to obtain direct evidence of co-ordinated regulation of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) and differentiation in tumour cells and to study some signalling pathways involved in joint regulation of these two cell phenotypes. The sublines of human melanoma (mS) and hepatoma (human HepG2 and rat McA RH 7777) cell lines were obtained by retroviral infection of the wild-type cells with the cDNA of the human retinoic acid receptor alpha (RAR alpha). The resulting sublines stably overexpressed exogenous RAR alpha gene. The infectants became more differentiated than the parental cells as determined by a decrease in the synthesis of the embryo-specific alpha-fetoprotein in HepG2 and McA RH 7777 hepatoma cells and by an increase in melanin synthesis in mS cells. The differentiation of human cells was accompanied by an increase in the amounts of MDR1 mRNA but not by an increase in P-gp activity as a drug transporter, in contrast, in the rat RAR alpha overexpressing cells P-gp functional activity was elevated. Treatment with cytotoxic drug (colchicine) or retinoic acid (RA) resulted in a slight increase in P-gp activity in the parental and RAR alpha-infected melanoma cells, whereas the increase in P-gp function in the infected hepatoma cells (both human and rat) was very prominent. Thus, we provide new evidence that cell differentiation caused by the overexpression of the gene participating in the differentiation programme leads to overexpression of MDR1 gene and drug resistance and that this effect is tissue and species specific. These data imply that the activation of the RA-controlled signalling pathway up-regulates MDR1 gene expression.
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PMID:Influence of exogenous RAR alpha gene on MDR1 expression and P-glycoprotein function in human and rodent cell lines. 966 38

P-glycoprotein (P-GP) is known to be a multidrug resistant 1 gene product and to exhibit resistance to a broad range of drugs including anticancer drugs such as epirubicin. Its overexpression is reported in human hepatocellular carcinoma and in adenomatous hyperplasia of the liver as well. In order to clarify the evolution of P-GP expression during hepatocarcinogenesis and its modulation by anticancer drugs, we performed an immunohistochemical study in male Wistar rat livers exposed to diethylnitrosamine (DEN) for 12 weeks. Some rats were pretreated with cisplatin or epirubicin 1 week prior to the exposure, and some rats were treated with them at the 10th week after the exposure. While there was no P-GP expression in the liver of the control, cisplatin, and epirubicin (DEN-free) rats, expression was confirmed in the hepatocytes of DEN-treated rats. The immunostaining of hyperplastic nodules was significantly more intense than in well-differentiated hepatocellular carcinomas, and no staining was observed in poorly-differentiated carcinomas. Markedly intense staining was observed in the early hyperplastic nodules of cisplatin-pretreated rats, as well as in epirubicin-pretreated rats. Plasma alpha-fetoprotein levels were markedly elevated in DEN-treated rats, while tumor necrosis factor-alpha levels were not. In conclusion, the results suggest that P-GP confers a protective effect against anticancer drugs and provides a great advantage to the initiated cells. Furthermore, in addition to epirubicin, cisplatin also promotes the induction of P-GP in the initiated cell.
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PMID:Expression of P-glycoprotein in rat hepatocarcinogenesis by diethylnitrosamine and the modulation by anticancer drugs. 1181 50

Despite improvement in liver surgery, patient prognoses after surgical resection for hepatocellular carcinoma (HCC) remain unsatisfactory. One of the obstacles in managing post-operative recurrence is resistance to chemotherapy. We examined the effect of Cepharanthin (CEP), a natural alkaloid extracted from Stephania cepharantha Hayata, in overcoming P-glycoprotein (P-gp)-associated doxorubicine (DOX) resistance, using 2 DOX-resistant HCC cell lines, and their DOX-sensitive parental cell lines. P-gp expression in surgically removed HCC tumours was also examined. In the in vitro study, overexpression of P-gp in the resistant cells was confirmed by immunoblotting and RT-PCR. Drug sensitivity testing with MTT assay showed that co-administration of CEP significantly enhanced cytotoxicity of DOX, but only in resistant cells. Flow cytometric analysis revealed that CEP significantly increased intracellular DOX concentration by inhibiting DOX efflux. P-gp expression in 107 patients with HCC was examined retrospectively by immunohistochemistry. P-gp was overexpressed in the tumours of 36% of these patients, especially in well-differentiated tumours that are often insensitive to chemotherapy, supporting the use of P-gp modulation as a new chemotherapeutic approach. Multivariate logistic regression analysis revealed that serum alpha-fetoprotein level was inversely related to P-gp expression. Our data suggest that co-administration of CEP with DOX may potentiate the effect of chemotherapy on drug-resistant HCC.
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PMID:Beneficial effect of cepharanthine on overcoming drug-resistance of hepatocellular carcinoma. 1476 48

Accumulation of doxorubicin (Dox), its conjugates with the second generation dendritic polymer (G2-Dox) and vector pro- tein (recombinant third domain of alpha-fetoprotein - 3D-G2- Dox) in normal and tumor cells was studied in vitro within the framework of the development of selective transport system of anticancer drugs to the target cells. The objects of the study were cells of peripheral blood mononuclear fraction of healthy donors and cells of breast adenocarcinoma lines MCF-7 and MCF-7/MDR1, differing in chemosensitivity. G2-Dox and 3D-G2-Dox accumulated in tumor cells of the both lines better than free Dox (p<0,05). However removal of these drugs out of cells MCF-7 and MCF-7/MDR1 was significantly different: in the latter case all free Dox was excluded from the cells for 24 hours while Dox, accumulated in composition with dendrimers, still remained in the cells. It was important that 3D-G2-Dox (unlike the G2-Dox) accumulated in normal cells worse than free Dox (p<0.01). Thus, the results indicate that the use of 3D-G2-Dox is the most promising because it accumulates in tumor cells better and in normal cells worse than free Dox. Furthermore it can be assumed that the use of 3D-G2-Dox would be especially useful in cases of multi-drug resistance associated with the high expression of P-glycoprotein.
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PMID:[Accumulation of doxorubicin conjugates with dendritic polymer and vector protein in normal and tumor cells in vitro]. 3069 94