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)

To identify the role of protein kinase C (PKC) isoforms in multidrug resistance in tumor cells, we examined the PKC isoform pattern in the multidrug resistant P388/ADR cell line and studied the effect of down regulation of PKC isoforms on intracellular daunorubicin accumulation and P-glycoprotein expression. Using monoclonal antibodies to PKC alpha, beta and gamma and flow cytometry technique we showed that P388/ADR cells overexpressed PKC alpha and beta as compared to drug sensitive P388 cells. Prolonged treatment of P388/ADR cells with phorbol myristate acetate (PMA), a procedure that is known to down regulate PKC, resulted in the down regulation of total PKC activity and the PKC beta isoform (at the protein level) that was accompanied by the correction of daunorubicin accumulation in P388/ADR cells. The level of expression of P-glycoprotein in PMA treated cells was similar to that of untreated cells. These results suggest that PKC beta regulates the drug efflux function of P-glycoprotein.
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PMID:Protein kinase C isoforms in multidrug resistant P388/ADR cells: a possible role in daunorubicin transport. 134 51

For investigation of relative differences in mRNA expression levels and of correlations in the expression of genes possibly involved in multidrug resistance (MDR) of acute myelogenous leukemias (AML), a complementary DNA polymerase chain reaction (cDNA-PCR) analysis was established for the genes encoding MDR1/P-glycoprotein, the multidrug resistance-associated protein (MRP), topoisomerase II alpha, topoisomerase II beta, topoisomerase I, glutathione S-transferase pi, protein kinase C (PKC) isozymes alpha, beta 1, beta 2, epsilon, eta, theta and cyclin A. In a first descriptive study comprising samples of childhood or adult AML we calculated the mean values from primary (n=14) or relapsed (n=23) states of the diseases, respectively. We found in the latter significant increases of MDR1, MRP, gst pi, and PKC theta gene expression. MDR1 and MRP gene expression levels were generally correlated (rs= +0.4128, P<0.02, n=37), as well as topoisomerase II alpha and cyclin A gene expression levels (rs= +0.8727, P<0.0001, n=35). Within the group of relapsed state AML a significant negative correlation between the gene expression levels of MDR1 and topoisomerase II alpha (rs= -0.5500, P<0.01, n=22) was observed. Remarkably, highly significant positive correlations were found for MDR1/PKC eta (rs= +0.5560, P<0.001, n=32), MRP/PKC theta (rs= +0.6573, P<0.0001, n=34) and MRP/PKC eta (rs= +0.5241, P<0.005, n=32).
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PMID:Expression of PKC isozyme and MDR-associated genes in primary and relapsed state AML. 864 57

Inhibition of protein kinase C (PKC) is discussed as a new approach for overcoming multidrug resistance (MDR) in cancer chemotherapy. For evaluation of this concept we applied the bisindolylmaleimide GF 109203X, which shows a highly selective inhibition of PKC isozymes alpha, beta 1, beta 2, gamma, delta and epsilon in vitro. The efficacy of this compound in modulation of MDR was examined using several P-glycoprotein (P-gp)-overexpressing cell lines including a MDR1-transfected HeLa clone, and was compared with the activities of dexniguldipine-HCI (DNIG) and dexverapamil-HC1 (DVER), both of which essentially act via binding to P-gp. As PKC alpha has been suggested to play a major role in P-gp-mediated MDR, cell lines exhibiting different expression levels of this PKC isozyme were chosen. On crude PKC preparations or in a cellular assay using a cfos(-711)CAT-transfected NIH 3T3 clone, the inhibitory qualities of the bisindolylmaleimide at submicromolar concentrations were demonstrated. At up 1 microM final concentrations of the PKC inhibitor GF 109203X, a concentration at which many PKC isozymes should be blocked substantially, no cytotoxic or MDR-reversing effects whatsoever were seen, as monitored by 72 h tetrazolium-based colorimetric MTT assays or a 90 min rhodamine 123 accumulation assay. Moreover, depletion of PKC alpha by phorbol ester in HeLa-MDR1 transfectants had no influence on rhodamine 123 accumulation after 24 or 48 h. MDR reversal activity of GF 109203X was seen at higher final drug concentrations, however. Remarkably, [3H]vinblastine-sulphate binding competition experiments using P-gp-containing crude membrane preparations demonstrated similar dose dependencies as found for MDR reversion by the three modulators, i.e. decreasing efficacy in the series dexniguldipine-HCl > dexverapamil-HCl > GF 109203X. Similar interaction with the P-gp in the micromolar concentration range was revealed by competition of GF 109203X with photoincorporation of [3H]azidopine into P-gp-containing crude membrane preparations. No significant effect of the PKC inhibitor on MDR1 expression was seen, which was examined by cDNA-PCR. Thus, the bisindolylmaleimide GF 109203X probably influences MDR mostly via direct binding to P-gp. Our work identifies the bisindolylmaleimide GF 109203X as a new type of drug interacting with P-gp directly, but does not support the concept of a major contribution of PKC to a P-gp-associated MDR, at least using the particular cellular model systems and the selective, albeit general, PKC inhibitor GF 109203X.
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PMID:Effects of the selective bisindolylmaleimide protein kinase C inhibitor GF 109203X on P-glycoprotein-mediated multidrug resistance. 882 55

Vitamin E is a mixture of eight compounds alpha, beta, gamma, delta- tocopherols and alpha, beta, gamma, delta- tocotrienols. Their individual role in cellular transport as antioxidants and in metabolic pathways has been highlighted in the present work. All the eight compounds have been docked with the respective metabolizing enzymes (alpha-tocopherol transfer protein (ATTP), alpha-tocopherol associated protein (TAP), P-glycoprotein (P-gly) and human serum albumin (HSA)) to understand molecular interactions for pharmacokinetics. These have been structurally aligned against the four human phospholipids in order to reveal their individual role in chylomicron formation and hence the mechanism of cellular transport. The study of their binding with their metabolizing enzymes provides insight to the comparative antioxidant activity of each of these isomers.
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PMID:Towards the interaction mechanism of tocopherols and tocotrienols (vitamin E) with selected metabolizing enzymes. 1970 94