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)

Protein phosphorylation is altered in multidrug resistant, reverse transformed Chinese hamster cells selected for resistance to vincristine (DC-3F/VCRd-5L) or actinomycin D (DC-3F/AD X), as compared to drug-sensitive parental DC-3F cells. Evidence for this was obtained by gel electrophoretic analysis of proteins phosphorylated in vitro in the presence of [gamma -32P]ATP. In general, the level of incorporation of 32P into resistant cell proteins was higher than into proteins of sensitive cells, when reactions were carried out in either the presence or absence of exogenous protein kinase modulators. Phosphorylation of P-glycoprotein a multidrug resistance-related protein, and of sorcin, a 22 kDa calcium-binding protein overproduced in many multidrug resistant cells including DC-3F/VCRd-5L, was demonstrated. Analysis of proteins metabolically labeled with [32P]-orthophosphate suggests that protein phosphorylation differences in cell-free extracts are representative of events in the intact cells. Data support the probability that a variety of kinase and/or phosphatase activities were altered in the multidrug resistant cells. These may be associated with resistance development, P-glycoprotein function, reverse transformation, state of differentiation, inhibition of cellular proliferation, or all of these components.
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PMID:Protein phosphorylation in multidrug resistant Chinese hamster cells. 257 75

Tumor cell resistance to doxorubicin (DOX) is usually associated with the overexpression of P-glycoprotein (PGP) in model systems. We have characterized the karyotypic changes in two sublines of HL-60 cells which differ in the induction of differentiation by retinoic acid. The parental sublines, designated HL-60A/S and HL-60Y/S, were selected in increasing concentrations of 0.025-0.1 micrograms/mL DOX. Monosomy 8 in HL-60Y/S was the only karyotypic difference prior to DOX exposure. Both sublines acquired 7q+ markers upon exposure to DOX. In HL-60Y/S, and add(7)(q21) replaced one homologue at 0.025 micrograms/mL DOX, and an add(7)(q32) appeared which replaced the other normal 7 at 0.05 micrograms/mL DOX. The HL-60A/S cells acquired an add(7)(q21) at 0.025 micrograms/mL DOX. The 7q+ abnormalities involved breakpoints in the midregion of 7q. The overexpression of phosphorylated PGP in immunoprecipitates with C-219 antibody was identified in both sublines of DOX-resistant HL-60 cells with 7q+ abnormalities, and this is consistent with the location of mdr-1 sequences to 7q21-21.1. Also, analysis of RNA from parental-sensitive and DOX-resistant sublines by reverse transcriptase-polymerase chain reaction revealed: a) comparable expression of multidrug resistance related protein (MPR) in sensitive and resistant sublines; and b) overexpression of mdr-1 only in the DOX-resistant sublines. Thus, the selection of DOX resistance in two sublines of HL-60 cells which differ in their response to retinoic acid-induced myeloid differentiation is reproducibly associated with overexpression of mdr-1 versus MRP.
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PMID:Acquisition of doxorubicin resistance in human leukemia HL-60 cells is reproducibly associated with 7q21 chromosomal anomalies. 860 35

Cellular expression of the multidrug transporter, P-glycoprotein (Pgp) is recognized as a biological mechanism possibly contributing to treatment failure in acute myeloid leukemia (AML). Correlative studies indicate its association with poor risk features including secondary AML, CD34+ surface phenotype, unfavorable karyotype and advanced age. Reported disparity in the prognostic impact of Pgp relates in part to variance in drug transport capacity. In Pgp expressing cells, capacity for drug extrusion is governed by maturation phenotype and is largely restricted to CD34+ populations lacking myeloid maturation antigens. Three competitive inhibitors of Pgp function showing promise in pilot studies, cyclosporin A (CsA), quinine and the cyclosporin D analogue PSC 833, have entered testing in phase III trials. The presence of non-Pgp-related mechanisms of multidrug resistance, relatively insensitive to Pgp modulators, may limit the success of such treatment strategies. Preliminary investigations indicate that overexpression of the gene encoding the multidrug resistance-related protein (MRP) occurs infrequently in de novo AML, but relative increases in gene message are evident in relapsed specimens. Overexpression of lung resistance protein (LRP) is associated with adverse prognostic variables such as age, secondary disease and Pgp, and has demonstrated prognostic relevance. Because treatment with Pgp modulators may select for this drug resistance phenotype, LRP merits evaluation in randomized trials of Pgp antagonists. These observations indicate that multiple biological mechanisms contribute to anthracycline resistance in AML, thereby warranting development of multifunctional modulators or chemotherapeutic agents with novel mechanisms of action.
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PMID:Role of multidrug resistance and its pharmacological modulation in acute myeloid leukemia. 866 48

In the present study organotypic multicellular spheroids (OMS) were used to study the effects of chemotherapeutic agents on malignant gliomas. Compared with the frequently used cell line models, OMS have several advantages with respect to the preservation of the cellular heterogeneity and the structure of the original tumour. OMS prepared from seven glioma specimens were treated with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), daunorubicin or doxorubicin. After exposure to these drugs, the histology and cell proliferation of the OMS were analysed by immunohistochemistry and image analysis. Furthermore, the expression of P-glycoprotein (P-gp) and multidrug resistance-related protein (MRP), which both can contribute to resistance to daunorubicin and doxorubicin, were immunohistochemically investigated. We found that OMS from gliomas are sensitive for daunorubicin and doxorubicin but not for BCNU in terms of tissue destruction and decrease in cell proliferation. In addition, all gliomas were P-gp and MRP negative, which is in accordance with the sensitivity for daunorubicin and doxorubicin. Considering the potential use of several new alternative drug delivery methods, such as intratumoural implantation of drug-impregnated polymers or liposomal encapsulation of cytostatic drugs, daunorubicin and doxorubicin might be effective in the treatment of malignant gliomas.
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PMID:Daunorubicin and doxorubicin but not BCNU have deleterious effects on organotypic multicellular spheroids of gliomas. 868 20

We have studied the relationship between expression of genes implicated in mediating resistance to cleavable complex-forming topoisomerase II (topo II) inhibitors and cellular sensitivity to ICRF-159, a 'catalytic' inhibitor of topo II. Overexpression of the membrane transporters, P-glycoprotein and multidrug resistance-related protein (MRP), or down-regulation of topo IIalpha and/or -beta, did not confer ICRF-159 resistance. Indeed, marked topo IIalpha down-regulation appeared to be associated with collateral sensitivity to ICRF-159. Our results indicate that the resistance mechanisms that pertain to cleavable complex-forming topo II inhibitors and ICRF-159 are distinct. The evidence presented here suggests that topo IIalpha, not topo IIbeta, is more likely to be the major in vivo target for ICRF-159.
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PMID:Response to ICRF-159 in cell lines resistant to cleavable complex-forming topoisomerase II inhibitors. 906 1

The liver is presented with a diverse set of nutrients, endogenous metabolites, and xenobiotics it must process for movement to their correct physiologic destinations. These compounds are transported by specific mechanisms that move their substrates, often against a concentration gradient. Several hepatic transporters have been identified such as the multispecific anion transporter, cMOAT, bile acid transporters, ion-motive ATPases, glutathione transporters, purine transporters, and the multidrug resistance-related protein, MRP. This review focuses on the hepatic regulation of the multidrug resistance genes that encode the P-glycoprotein transporters. P-glycoproteins are ATP-dependent integral membrane proteins that have diverse functions such as conferring resistance toward chemotherapeutic drugs and phospholipid movement. The expression of the multidrug resistance genes is regulated in a tissue-specific pattern and can be induced by exposure to chemotherapeutic drugs as well as cytotoxic xenobiotics. The specific molecular mechanisms that govern expression of these genes in normal and neoplastic cells are currently being unraveled.
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PMID:Hepatic canalicular membrane 4: expression of the multidrug resistance genes in the liver. 914 96

Podophyllotoxin and epipodophyllotoxin react with tubulin at the same binding site as colchicine, but in contrast to colchicine, do not appear to exert their cytotoxicities by mechanisms dependent on P-glycoprotein (Pgp) expression. To investigate structural requirements for Pgp recognition a series of podophyllotoxin and epipodophyllotoxin derivatives have been synthesized. Their interactions with the multidrug resistance-related protein Pgp have been studied by evaluating their relative cytotoxicities versus P388-sensitive murine leukemic cells and a classic multidrug-resistant (MDR) Pgp-overexpressing subline (P388/ADR), and their relative tubulin polymerization inhibitory activities against microtubular proteins have been determined. Based on tridimensional structure-activity relationships within this series of compounds, structural requirements for Pgp recognition have been identified. Moreover, proposals are made for extending these criteria to other chemical classes of anticancer drugs.
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PMID:Requirements for P-glycoprotein recognition based on structure-activity relationships in the podophyllotoxin series. 962 71

To identify prognostic factors alternative or additional to P-glycoprotein (Pgp), we studied the impact of the multidrug resistance-related protein (MRP), bcl-2 (flow cytometry), mutant p53 (single-strand conformation polymorphism), and heat-shock protein 27 (HSP27, Western blotting) in myeloid blasts obtained at the time of diagnosis in patients with de novo acute myeloid leukemia (AML). We collected bone marrow samples from untreated AML patients, prepared the cells as well as the cellular protein, and froze all the material. We then analyzed 20 patients who responded with complete remission (CR) and 20 patients who had blast persistence (BP). The purpose of the study was to determine whether leukemic blasts from patients with BP were more resistant to chemotherapy than those from patients with CR. There was no significant correlation between the expression of any of these proteins alone and treatment outcome in both groups studied. In contrast, there was a significant correlation between the coexpression of at least two of these proteins and response (p = 0.0298), which turned out to be a significant independent prognostic factor for treatment failure (p = 0.0329, relative risk = 1.5) according to multivariate analysis. We conclude that drug resistance in AML is multifactorial. Thus, coexpression of different resistance mechanisms may be responsible for the primary drug resistance in de novo AML.
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PMID:In acute myeloid leukemia, coexpression of at least two proteins, including P-glycoprotein, the multidrug resistance-related protein, bcl-2, mutant p53, and heat-shock protein 27, is predictive of the response to induction chemotherapy. 980 49

MDR1 P-glycoprotein (Pgp), the product of the MDR1 gene involved in multidrug resistance in cancer cells, is also expressed in normal tissues. In the human kidney, it is localized in the mesangium, the proximal tubule, the thick ascending limb of Henle's loop, and the collecting duct. Pgp actively transports lipophilic xenobiotics, peptides, steroids, and lipids, and perhaps endogenous substrates. It has been shown previously that human mesangial cells in culture express active Pgp and that the expression of Pgp can be down-regulated by exposure to antisense oligonucleotides. Mesangial cells do not express multidrug resistance-related protein (MRP). Experiments were performed to determine whether 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (generically platelet-activating factor, PAF) is a substrate of Pgp in human mesangial cells in culture. This study found: (1) PAF C-16 and analogs inhibited Pgp-mediated efflux of rhodamine 123 by 59 to 88% in multidrug-resistant KBV-1 cells and by 85 to 97% in cultured human mesangial cells. (2) In mesangial cells stimulated with A23187, the secretion of endogenously produced PAF was inhibited by >80% by the Pgp blockers verapamil, cyclosporin A, PSC-833, vinblastine, and adriamycin. (3) Preincubation with MDR1 antisense oligonucleotides also blocked PAF secretion by human mesangial cells. PAF analogs do not modify the transport of MRP substrates in MCF-7/VP cells expressing MRP but not Pgp. These results indicate that PAF is an endogenous substrate of Pgp in human mesangial cells. Inhibition of Pgp transport may be useful in reducing glomerular damage occurring in pathologic conditions where PAF secretion is elevated.
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PMID:Secretion of platelet-activating factor is mediated by MDR1 P-glycoprotein in cultured human mesangial cells. 1054 Dec 89

1. The blood-brain barriers restrict the passive diffusion of many drugs into the brain and constitute a significant obstacle in the pharmacological treatment of central nervous system diseases and disorders. The degree of restriction they impose is variable, with some lipid-insoluble drugs effectively excluded from the brain, while many lipid-soluble drugs do not appear to be subject to any restriction. 2. The ease with which any particular drug diffuses across the blood-brain barrier is determined largely by the number and strength of intermolecular forces "holding" it to surrounding water molecules. By quantifying the molecular features that contribute to these forces, it is possible to predict the in vivo blood-brain barrier permeability of a drug from its molecular structure. Dipolarity, polarizability, and hydrogen bonding ability are factors that appear to reduce permeability, whereas molecular volume (size) and molar refraction are associated with increased permeability. 3. Increasing the passive entry of "restricted" drugs into the central nervous system can be achieved by disrupting the blood-brain barrier (increased paracellular diffusion) or by modifying the structure of "restricted" drugs to temporarily or permanently increase their lipid solubility (increased transcellular permeability). 4. Competitive inhibition of outwardly directed active efflux mechanisms (P-glycoprotein and MRP, the multidrug resistance-related protein) can also significantly increase the accumulation of certain drugs within the central nervous system.
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PMID:Determinants of passive drug entry into the central nervous system. 1069 12


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