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)

8-Cl-cAMP, a site-selective analogue of cAMP, decreased mdr-1 expression in multidrug-resistant human breast cancer cells. A sixfold reduction of mdr-1 mRNA expression by 8-Cl-cAMP began within 8 h of treatment and was associated with a decrease in the synthesis of P-glycoprotein and with an increase in vinblastine accumulation. A reduction in mdr-1 expression after 8-Cl-cAMP treatment was also observed in multidrug-resistant human ovarian cancer cell lines. 8-Cl-cAMP is known to change the ratio between the two regulatory subunits, RI and RII, of protein kinase A (PKA). We observed that RI alpha decreased within 24 h of 8-Cl-cAMP treatment, that RII beta increased after as few as 3 h of treatment, and that PKA catalytic activity remained unchanged during 48 h of 8-Cl-cAMP treatment. The results are consistent with the hypothesis that mdr-1 expression is regulated in part by changes in PKA isoenzyme levels. Although 8-Cl-cAMP has been used to differentiate cells in other model systems, the only differentiating effect that could be detected after 8-Cl-cAMP treatment in the MCF-7TH cells was an increase in cytokeratin expression. Evidence that the reduction of mdr-1 mRNA occurred at the level of gene transcription was obtained by measuring chloramphenicol acetyltransferase (CAT) mRNA in MCF-7TH cells transfected with an mdr-1 promoter-CAT construct prior to 8-Cl-cAMP treatment. Thus, 8-Cl-cAMP is able to downregulate mdr-1 expression and suggests a new approach to reversal of drug resistance in human breast cancer.
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PMID:Downregulation of mdr-1 expression by 8-Cl-cAMP in multidrug resistant MCF-7 human breast cancer cells. 754 90

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

From an undifferentiated soft tissue sarcoma (STS) a cell line designated US8-93 has been established. At subcloning the cell line US8-93 three different lines (US8-93A, B and C) could be set up. In a subsequent study characteristics for ultrastructure, growth, cell cycle distribution, karyotype, protein overexpression detected by immunohistochemistry (IHC) and p53 mutational status were determined. The cell line US8-93 as well as subclones contain mainly bipolar spindle-shaped cells and additionally some polygonal and multinucleated cells. Cells possess the characteristics of primitive mesenchymal cells based on their positive reactions with anti-vimentin and negative reactions for desmin, cytokeratin, myoglobin, S100, and NSE, implying a classification as an undifferentiated STS. Cytogenetic analysis revealed nearly diploid cells with several structural and numerical aberrations for chromosomes 1, 3, 4, 6, 9, 10, 12, 13, 15 and 18. IHC positivity was found for the tumor suppressor proteins p53 and Rb, the oncogene products Bcl-2, K-ras, N-ras, P-glycoprotein Mdr-1 and MDM-2. In the p53 gene a nonsense mutation in exon 4 was detected, that was confirmed in the original primary tumor and in three derivative clonal lines. The described STS cell line represents a valuable supplementation to the relatively small number of human STS cell lines currently available and may also provide a good in vitro model for studies of STS tumorigenesis in respect to a mutated p53 gene.
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PMID:Morphological and molecular characterization of an undifferentiated soft tissue sarcoma cell line and derivative clones. 2152 41