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)

The K562/VCR cell line, exhibiting acquired multidrug resistance (MDR) with increased expression of a cell surface glycoprotein (P-glycoprotein), was isolated from human erythroleukemia K562 cells. Various compounds that induced erythroid differentiation of K562 cells were tested for their effects on growth and differentiation of these K562/VCR cells. Sodium butyrate, hemin, 1-beta-D-arabinofuranosylcytosine, and erythroid differentiation factor (EDF) induced erythroid differentiation of K562/VCR cells as well as K562 cells. The MDR of K562/VCR cells was partly overcome by treatment with EDF but not with the other inducers. Expression of P-glycoprotein by K562/VCR cells was measured by radioimmunoassay using MRK16 monoclonal antibody. Results showed that EDF caused down-regulation of P-glycoprotein in K562/VCR cells, whereas the other inducers did not cause its down-regulation. Thus, in addition to inducing erythroid differentiation, EDF enhanced the sensitivity of K562/VCR cells to multidrugs and suppressed expression of P-glycoprotein. These results suggest that differentiation inducers may be useful in chemotherapy of leukemic MDR cells.
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PMID:Inhibition by erythroid differentiation factor (activin A) of P-glycoprotein expression in multidrug-resistant human K562 erythroleukemia cells. 167 36

The BCR/ABL tyrosine kinase inhibitor, imatinib, has shown substantial effects in blast crises of chronic myelogenous leukemia. However, most patients relapse after an initial clinical response, indicating that drug resistance is a major problem for patients being treated with imatinib. In this study, we generated a new imatinib-resistant BCR/ABL-positive cell line, KCL22/SR. The 50% inhibitory concentration of imatinib was 11-fold higher in KCL22/SR than in the imatinib-sensitive parental cell line, KCL22. However, KCL22/SR showed no mutations in the BCR/ABL gene and no increase in the levels of BCR/ABL protein and P-glycoprotein. Furthermore, the level of phosphorylated BCR/ABL protein was suppressed by imatinib treatment, suggesting that mechanisms independent of BCR/ABL signaling are involved in the imatinib resistance in KCL22/SR cells. DNA microarray analyses demonstrated that the signal transduction-related molecules, RAS p21 protein activator and RhoA, which could affect Ras signaling, and a surface tumor antigen, L6, were upregulated, while c-Myb and activin A receptor were downregulated in KCL22/SR cells. Furthermore, imatinib treatment significantly suppressed the level of phosphorylated p44/42 in KCL22 cells but not in KCL22/SR cells, even when BCR/ABL was inhibited by imatinib. These results suggest that various mechanisms, including disturbance of Ras-mitogen-activated protein kinase signaling, are involved in imatinib resistance.
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PMID:Analysis of gene expression profiles in an imatinib-resistant cell line, KCL22/SR. 1274 26

To develop a novel in vitro system for predicting intestinal drug absorption using human induced pluripotent stem (iPS) cell-derived intestinal epithelial cells, the cells need to have sufficient drug-metabolizing enzyme and drug transporter activities. We found that cyclic adenosine monophosphate (cAMP) signaling plays an important role in the differentiation of human iPS cells into intestinal epithelial cells. In this study, we aimed to demonstrate the effects of signaling activation in the intestinal differentiation of human iPS cells and the pharmacokinetic characteristics of human iPS cell-derived intestinal epithelial cells. Human iPS cells were differentiated into intestinal stem cells using activin A and fibroblast growth factor 2. Subsequently, the intestinal stem cells were maturated into intestinal epithelial cells by treatment with 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP) and 3-isobutyl-1-methylxanthine (IBMX), which activate cAMP signaling. The expression levels of intestinal markers and pharmacokinetics-related genes in the differentiated cells were markedly increased by using 8-Br-cAMP and IBMX. In the cells differentiated with the compound we observed cytochrome P450 (CYP) 3A4 inducibility via pregnane X receptor and vitamin D receptor. The metabolic activities of CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, and UDP-glucuronosyltransferase, which are expressed in the human small intestine, were also markedly increased. Furthermore, uptake of glycylsarcosine via peptide transporter 1 was markedly increased. The cells differentiated with the compounds also had drug transporter activities via organic anion transporters and P-glycoprotein. This study is the first to report that the activation of cAMP signaling promotes differentiation of human iPS cell-derived intestinal epithelial cells.
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PMID:Cyclic AMP Signaling Promotes the Differentiation of Human Induced Pluripotent Stem Cells into Intestinal Epithelial Cells. 3006 21