Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 52-year-old woman, previously treated with chemo- and radiotherapy for Hodgkin's disease, developed an acute non-lymphoid leukemia and, contemporarily, an IgG-kappa paraproteinemia. Cytogenetic analysis showed a major clone, representing 90% of observed metaphases, with monosomy of chromosomes 5 and 14. In addition, leukemic cells exhibited a high expression of the P-glycoprotein, a transmembrane glycoprotein involved in the multidrug-resistance mechanism. Possible explanations for this cluster of findings are provided.
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PMID:Simultaneous occurrence of monoclonal gammopathy and acute secondary leukemia with overexpression of P-glycoprotein. 136 21

Multidrug-resistance (MDR) in neoplastic cells is frequently characterized by the overexpression of P-glycoprotein (PGP), a 170 kDa transmembrane glycoprotein that binds multiple cytotoxic drugs as well as calcium channel antagonists. Chloroquine resistance in Plasmodium falciparum appears to be analogous to MDR in neoplastic cells, where the induction of resistance with one drug confers resistance to other structurally and functionally unrelated drugs. To test the hypothesis that chloroquine resistance in P. falciparum and antimony resistance in Leishmania is mediated by a similar mechanism of MDR in mammalian neoplastic cells, a PGP-specific monoclonal antibody (C219) was used to determine the presence of PGP genes in resistant and sensitive Plasmodium and Leishmania parasites by indirect immunofluorescence assays and Western blotting procedures. These PGP-like components were detected in both drug-sensitive and -resistant Plasmodium and Leishmania cells. A 40-42 kDa component was observed to be greater in a chloroquine-resistant P. berghei (C line) than in a chloroquine-susceptible P line. Differences observed between Pentostam-resistant and -sensitive Leishmania promastigote clones and isolates included the increased expression of 96-106 and 23-25 kDa peptides in drug-resistant L. enrietti, and increased amounts of two different peptides in two drug-resistant L. panamensis clones (i.e., 96-106 and 43-45 kDa in WR-746-CL4, and 53 and 23-25 kDa in kDa) in amastigotes as in MDR KB carcinoma cells (KB-V1). Comparative indirect immunofluorescent studies suggested that a correlation existed between the degree of antimony susceptibility and the concentration of the moiety recognized by C219 in two L. panamensis clones. Binding of the C219 monoclonal antibody to the PGP-like component of Leishmania was blocked by Pentostam, while the binding of C219 to multiple-drug resistant KB-V1 PGP was not inhibited by Pentostam, regardless of the PGP concentration. This suggests some degree of specificity in the binding of Pentostam to the Leishmania PGP-like components. In addition, these studies have demonstrated that drug-sensitive Leishmania accumulate two to five times more 125Sb-Pentostam than resistant clones.
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PMID:Characteristics of multidrug resistance in Plasmodium and Leishmania: detection of P-glycoprotein-like components. 167 53

The MDR P-glycoprotein has been described as a major factor of multidrug resistance. This transmembrane glycoprotein acts like an energy dependent efflux pump which possesses a broad specificity. It seems to be acting as a pump requiring drug fixation prior to extrusion. With the aim of investigating which parameters influence the recognition of drugs by the MDR system, we have determined the toxicities of different drugs on human and murine sensitive and resistant cell lines. For this purpose we have isolated and characterized a human adriamycin-resistant cell line, CEM/Adr, which presents an MDR phenotype. The tested drugs were ellipticine and olivacine derivatives which differ through discrete lateral chain substitutions. The influence of lateral chain lipophilicity and nitrogen quaternarization on drug recognition was studied. Small modifications in the chemical structure of the drugs have induced large changes in their toxicities and in the cross-resistance levels of the MDR cells to the tested compounds. The cross-resistances of the murine and human cells to the various compounds were strikingly different. The validity of murine screening models in the selection of anti-tumor drugs for human therapy must therefore be questioned.
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PMID:Comparative cytotoxicities of a series of ellipticine and olivacine derivatives on multidrug resistant cells of human and murine origins. 198 10

Gp170 (also known as P-glycoprotein) is a transmembrane glycoprotein which is overexpressed in multidrug-resistant tumor cells and is also found in the apical plasma membrane domain of several normal human and animal tissues. Gp170 has been postulated to function as an energy-dependent efflux pump for cytotoxic drugs. In rat liver, Gp170 is restricted to the bile canalicular domain of the plasma membrane. Canalicular membrane vesicles (CMV), but not sinusoidal membrane vesicles, contained a approximately 160-kDa protein which reacts with anti-Gp170 monoclonal antibody and manifest ATP-dependent [3H]daunomycin transport which is temperature dependent, osmotically sensitive, and saturable. Among several nucleotides, ATP was a potent stimulator of transport whereas non- or slowly hydrolyzable analogues (adenosin-5-O-(3-thiotriphosphate, adenyl-5-yl-imidodiphosphate) were ineffective. ATP-dependent daunomycin transport was inhibited by cytotoxic drugs (vinblastine, vincristine, and adriamycin) and other drugs, such as verapamil and quinidine, which restore anti-cancer drug sensitivity in resistant cells. Inside-out CMV were separated from right side-out CMV by antibody-induced affinity density perturbation. Only inside-out CMV manifested ATP-dependent daunomycin transport. These results suggest that Gp170 is an ATP-dependent efflux pump which is responsible for the undirectional, energy-dependent transport of daunomycin and other drugs by rat liver into the bile.
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PMID:The function of Gp170, the multidrug resistance gene product, in rat liver canalicular membrane vesicles. 256 55

Multidrug resistant (MDR) phenotype is characterized by a defect in drug accumulation caused by overexpression of a transmembrane glycoprotein, the P-glycoprotein (P-gp). MDR phenotype can be characterized either with monoclonal antibodies raised against P-gp or with functional tests, most often based on the incorporation of fluorescent compounds. In the present study, data obtained with the monoclonal antibodies C219, JSB1 and MRK16 are compared to those of functional tests performed by flow cytometry including uptake of daunorubicin (DNR), Rhodamine 123 (Rh 123) or Hoechst 33342. Sensitive and resistant cell lines K562S, K562R, KBA1 and KB31, derived either from a human chronic myeloid leukemia or from a human epithelial carcinoma, were used. In resistant cells, P-gp expression was revealed with either the monoclonal antibodies C219, JSB1 or MRK-16. The most specific results were obtained with MRK-16. With functional tests, no matter which dyes were used, the fluorescence was always stronger in sensitive than in resistant cells. However, with DNR and Hoechst 33342, an incorporation of these dyes was exhibited in resistant cells. This phenomenon was not observed with Rh 123, which makes it possible to distinguish clearly between sensitive and resistant cells and to detect as few as 1% of resistant cells. Because of its high sensitivity, the functional test involving incorporation of Rh 123 was successfully used in acute myeloid leukemia to detect multichemoresistant cells.
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PMID:Evaluation of multidrug resistant phenotype by flow cytometry with monoclonal antibodies and functional tests. 765 50

P-glycoprotein (P-gp) is a transmembrane glycoprotein responsible for the multidrug resistant (MDR) phenotype in various cancer cells. It has been shown that P-gp transports various kinds of anti-cancer agents as well as hydrophobic chemicals. Although P-gp is also expressed in normal human tissues, such as liver, kidney, and adrenal gland, its function and transporting substrates in these tissues are still unknown. In previous work, we demonstrated that some compounds in human plasma modulate the transporting activity of P-gp. We also found that P-gp is expressed at a high level in the bovine adrenal gland and that this tissue contains large amount of compounds which inhibit the transporting activity of P-gp. We purified such compounds from the adrenal gland by monitoring the ability to enhance the accumulation of [3H]vincristine in MDR cells. Two major compounds were purified and identified as progesterone and pregnenolone by nuclear magnetic resonance (NMR) analysis. Progesterone was the most potent and abundant compound that inhibited the transporting activity of P-gp among the compounds extracted from bovine adrenal gland with methanol. We also found that six authentic progesterone metabolites in the 5 beta-metabolic pathway but none in the 5 alpha-metabolic pathway were able to enhance the accumulation of [3H]vincristine in MDR cells and to inhibit [3H]azidopine photolabeling of P-gp in the adrenal gland. These results indicate that some progesterone metabolites can interact with P-gp and that stereoisomerism around carbon 5 of the progesterone metabolites is important for them to be recognized by P-gp.
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PMID:Progesterone and its metabolites: the potent inhibitors of the transporting activity of P-glycoprotein in the adrenal gland. 790 38

Multidrug resistance is a major clinical problem in chemotherapy of malignant disease. Acute megakaryoblastic leukemia (AMKL) is a rare form of childhood leukemia, and is often more resistant to many anticancer chemotherapeutic drugs compared to other types of childhood leukemia. There have been reports of the increased expression in hematologic malignancy of multidrug resistant (mdr-1) gene, which encodes for a transmembrane glycoprotein P-glycoprotein that acts as an efflux pump for structurally unrelated chemotherapeutic drugs. We investigated the malignant cells of 15 newly diagnosed childhood AMKL patients by immunocytochemical analysis and found P-glycoprotein expression in all samples from these patients. RNA prepared from five patients at the time of presentation confirmed the expression of mdr-1 specific message in all cases by Northern blot analysis. These results imply that malignant cells from all childhood AMKL might express the mdr-1/P-glycoprotein.
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PMID:Expression of MDR-1/P-glycoprotein in childhood acute megakaryoblastic leukemia cells. 859 Aug 43

The occurrence of multidrug resistance (MDR) is one of the main obstacles in the successful chemotherapeutic treatment of cancer. MDR cell lines are resistant to the so-called naturally occurring anti-cancer drugs, such as anthracyclines, Vinca alkaloids and epipodophyllotoxins, but are not cross-resistant to alkylating agents, antimetabolites and cisplatin. So far, three separate forms of MDR have been characterized in more detail: classical MDR, non-Pgp MDR and atypical MDR. Although all three MDR phenotypes have much in common with respect to cross-resistance patterns, the underlying mechanisms certainly differ. Atypical MDR is associated with quantitative and qualitative alterations in topoisomerase II alpha, a nuclear enzyme that actively participates in the lethal action of cytotoxic drugs. Atypical MDR cells do not overexpress P-glycoprotein, and are unaltered in their ability to accumulate drugs. In this review we will focus on classical and non-Pgp MDR. The molecular mechanism of classical and non-Pgp MDR is transcriptional activation of membrane-bound transport proteins. These transport proteins belong to the ATP-binding cassette (ABC) superfamily of transport systems. The classical MDR phenotype is characterized by a reduced ability to accumulate drugs, due to activity of an energy-dependent uni-directional, membrane-bound, drug-efflux pump with broad substrate specificity. The classical MDR drug pump is composed of a transmembrane glycoprotein (P-glyco-protein-Pgp) with a molecular weight of 170 kD, and is, in man, encoded by the so-called multidrug resistance (MDR1) gene. Typically, non-Pgp MDR has no P-gly-coprotein expression, yet has about the same cross-resistance pattern as classical MDR. This non-Pgp MDR phenotype is caused by overexpression of the multidrug resistance-associated protein (MRP) gene, which encodes a 190 kD membrane-bound glycoprotein (MRP). MRP probably works by direct extrusion of cytotoxic drugs from the cell and/or by mediating sequestration of the drugs into intracellular compartments, both leading to a reduction in effective intracellular drug concentrations. For the classical MDR phenotype, evidence is accumulating that it plays a role indeed, in clinical drug resistance, especially in some hematological malignancies (acute myeloid leukemia, multiple myeloma and non-Hodgkin's lymphoma) and solid tumors (soft tissue sarcomas and neuroblastoma). The association of MRP with clinical drug resistance has not been elaborated, yet, and studies on MRP expression in human cancer have just begun. We found that overexpression of MRP, as determined by RNase protection assay as well as by immunohistochemistry, occurs in several human cancers, among which are cancer of the lung, esophagus, breast and ovary, and leukemias. Further studies are indicated to establish whether elevated MRP expression at diagnosis is an unfavorable prognostic factor for clinical outcome of chemotherapy.
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PMID:Molecular mechanisms of multidrug resistance in cancer chemotherapy. 888 Aug 78

Multidrug-resistant (MDR) cells are characterized by a defect in drug accumulation caused by overexpression of a transmembrane glycoprotein, the P-glycoprotein (P-gp). The MDR phenotype can be characterized either by use of monoclonal antibodies raised against P-gp or with functional tests based on the intracellular accumulation of fluorescent molecules. The aim of the present study was to compare the effectiveness of functional tests performed by flow cytometry including uptake of daunorubicin (DNR) (2 micrograms/ml), Hoechst 33342 (5 micrograms/ml), or rhodamine 123 (RH 123) (0.1 microgram/ml); and to evaluate the effect of cell death induced by heating at 60 degrees C for 2 h on incorporation of DNR and RH 123. Sensitive and resistant human hematopoietic K 562 cells expressing P-gp were identified by monoclonal antibodies C 219 and MRK-16. Fluorescence of the dyes was always higher in sensitive than in resistant cells. However, DNR and Hoechst 33342 produced a slight incorporation in resistant cells, while RH 123 showed lack of incorporation in resistant cells. Thus, RH 123 allows sensitive and resistant cells to be clearly distinguished. In case of cell death, accumulation of RH 123 and DNR were different. With RH 123, fluorescence intensity strongly decreased in sensitive cells. With DNR, fluorescence intensity was enhanced in resistant cells. Thus, when the MDR phenotype is defined by uptake of DNR or RH 123, artifactual results due to cell death may be avoided by using a dye such as propidium iodide to eliminate dead cells.
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PMID:Flow cytometry evaluation of the multidrug-resistant phenotype with functional tests involving uptake of daunorubicin, Hoechst 33342, or rhodamine 123: a comparative study. 892 22

Due to the close homology between bacterial and tumor cell transporter proteins, some antiplasmid and anticancer compounds were tested for their ability to reserve the multidrug resistance (mdr) of lymphoma cells. Some known anticancer medicines such as platidiam, novantron, fluorouracil, bleomycin and methotrexate were ineffective/while vinca alkaloids exerted a strong reversal effect on the mdr of lymphoma cells. The structurally related reserpine and yohimbine do not affect the activity of efflux pump. Some selected antitumor phenothiazines and benzo[a]phenothiazines, including trifluoperazine inhibit the P-glycoprotein (pgp) function. This fact is independent from the antiproliferative- or differentiation inducing effects. Since the polylactosamine specific tomato lectin prevents the action of the chemosensitizers tested, it is supposed that the site of action of phenothiazines can be at the 1st loop in the transmembrane glycoprotein. The efflux pump activity of the pgp in brain capillary endothel which is responsible for blood brain barrier (BBB) was also inhibited by some phenothiazines. However, the tomato lectin sensitivity of pgp was different in mouse lymphoma and human brain capillary endothelial cells. The mdr-gene expression of the mouse lymphoma cells (which were transfected with the human mdr-1 gene) could be reduced by phenothiazines such as promethazine and trifluoperazine, when the cells were cultured in the presence of 0.5 microgram/mL phenothiazines. Further synergism was found between two resistance modifiers i.e. verapamil and trifluoperazine on the inhibition of mdr-glycoprotein.
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PMID:Multidrug resistance reversal in mouse lymphoma cells by heterocyclic compounds. 971 5


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