Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Modulation of the expression of P-glycoprotein, a plasma membrane protein associated with multidrug resistance, was examined in drug-sensitive and drug-resistant tumor cells treated with leukoregulin, a M(r) 50,000 cytokine from human lymphocytes that rapidly permeabilizes the plasma membrane of many tumor cells facilitating the uptake of doxorubicin and other tumor-inhibitory antibiotics. P-glycoprotein expression was measured flow cytometrically by the binding of C219 or MRK16 monoclonal antibody to multidrug-sensitive human K562 erythroleukemia and 8226/S myeloma cells, compared to multidrug-resistant 8226/DOX40 myeloma cells. Cells were treated for up to 2 h with up to 80 units of leukoregulin/ml or one of a variety of unrelated cytokines including interleukin 1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, colony-stimulating factor, macrophage colony-stimulating factor, granulocyte macrophage colony-stimulating factor, tumor necrosis factor alpha, gamma-interferon, alpha-interferon, epidermal growth factor, platelet-derived growth factor AA, platelet-derived growth factor BB, insulin-like growth factor I, insulin-like growth factor II, fibroblast growth factor, or transforming growth factor beta. Leukoregulin caused a concentration-dependent decrease in P-glycoprotein expression; however, P-glycoprotein expression was unaffected by the other cytokines (< 12% decrease in expression). Leukoregulin-induced membrane permeabilization, determined flow cytometrically by intracellular fluorescein efflux, and decreased P-glycoprotein expression occurred simultaneously within 15 min in drug-sensitive and -resistant cells. Enhanced doxorubicin uptake, measured flow cytometrically by doxorubicin influx, was also present within 15 min. Leukoregulin enhancement of doxorubicin uptake and increased membrane permeability varied directly with the decrease in P-glycoprotein expression. Leukoregulin in combination with doxorubicin enhanced the inhibition of cell proliferation in 8226/DOX40 multidrug-resistant cells over expressing P-glycoprotein. In contrast, combined treatment of HL-60/MX2 multidrug-resistant human promyelocytic leukemia cells that do not overexpress P-glycoprotein in association with their multidrug resistance resulted in no greater growth inhibition than observed with HL-60/MX2 cells treated with doxorubicin alone. This is the first demonstration that a naturally occurring macromolecule with anticancer activities can modulate the expression of P-glycoprotein concomitant with enhanced drug uptake and inhibition of cell proliferation.
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PMID:Decreased P-glycoprotein expression in multidrug-sensitive and -resistant human myeloma cells induced by the cytokine leukoregulin. 135 22

Anti-P-glycoprotein antibody (MRK-16)-dependent cell-mediated cytotoxicity (ADCC) by blood mononuclear cells (MNC) was examined in patients with small cell lung cancer (SCLC) before and after systemic chemotherapy. The effect of in vitro treatment of MNC with interleukin (IL)-2 and macrophage-colony-stimulating factor (M-CSF) was also examined. The ADCC reaction was assessed by a 6 h 51Cr-release assay using a multidrug-resistant (MDR) SCLC cell line (H69/VP cells). The MRK-16 monoclonal antibody was able to augment spontaneous cytotoxicity by MNC, even in SCLC patients. Pretreatment of MNC with IL-2 significantly augmented their ADCC ability in SCLC patients, while M-CSF had no effect on ADCC activity. After the first cycle of systemic chemotherapy, the ADCC activity tended to decline, but ADCC of MNC pretreated with IL-2 was not affected. The results suggest that anti-P-glycoprotein antibody, in combination with a cytokine such as IL-2, may be therapeutically useful against human SCLC resistant to chemotherapeutic drugs.
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PMID:Influence of systemic chemotherapy on anti-P-glycoprotein antibody-dependent cell-mediated cytotoxicity in patients with small cell lung cancer. 766 88

Despite substantial advances in the surgery, radiotherapy and chemotherapy of gliomas, the prognosis of patients with glioblastomas has still not improved. Disappointing results in chemotherapy of glioblastomas resulting from multi-drug resistance (MDR) prompted us to investigate the influence of cytokine gene transfer in glioblastoma cells on the expression of P-glycoprotein and on chemosensitivity of transduced cells. Several investigations have shown that malignant gliomas express P-glycoprotein at high levels. The P-glycoprotein is a product of the multi-drug resistance gene (mdr1) and functions as an energy-dependent efflux pump which decreases drug accumulation and cytotoxicity. Since tumour necrosis factor alpha (TNF alpha) is a powerful anti-cancer agent used in clinical trials and gene therapy protocols, this cytokine gene was chosen for the present investigations. Transduction of the human TNF alpha (hTNF) gene carrying retroviral vector pN2tk-hTNF into U373MG human glioblastoma cells resulted in expression and secretion of biologically active hTNF. Release of transduced hTNF reduces P-glycoprotein expression and is associated with enhanced rhodamine-123 uptake and potentiation of cytotoxicity of the MDR-relevant drugs vincristine and doxorubicin. Furthermore, the transfected cell clones showed a reduced growth rate compared to the parental cells.
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PMID:Gene transfer of human TNF alpha into glioblastoma cells permits modulation of mdr1 expression and potentiation of chemosensitivity. 779 Jan 19

P-glycoprotein, a 170-kd glycoprotein encoded by the MDR 1 gene, is a member of a highly conserved superfamily of ATP-binding cassette (ABC) transport proteins. It shares extensive homology with numerous bacterial and eukaryotic ABC transport proteins. P-glycoprotein acts as an energy-dependent efflux pump that appears to transport structurally diverse agents ranging from ions to peptides. P-glycoprotein (P-gP) has been implicated as playing a role in multidrug (MDR) resistance in cancer, chloroquine-resistant Plasmodium falciparum infection, and possibly human immunodeficiency virus-1 (HIV-1) resistance to nucleoside compounds. A number of normal tissues in humans and rodents have been shown to express high levels of P-gp. The expression and function of P-gp in cells of the immune system have been explored in the past 2 years. This review presents a state of the art regarding the expression, regulation, and function of Pgp in cells of the immune system. In addition, its alteration in aging and HIV-1 infection is reviewed. A possible physiologic role of P-gp in cytokine secretion, antigen processing/presentation, and effector functions is also discussed.
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PMID:P-glycoprotein (MDR 1 gene product) in cells of the immune system: its possible physiologic role and alteration in aging and human immunodeficiency virus-1 (HIV-1) infection. 790 61

The ability of malignant cells to survive exposure to cytotoxic agents is a major obstacle to cure in patients with cancer. Multidrug resistance and the expression of P-glycoprotein are emerging as a cause of chemotherapy failure. Immunologic effector cells such as lymphokine-activated killer (LAK) cells or cytokine-induced killer (CIK) cells are capable of killing a broad range of tumor cell lines or freshly isolated tumor cells. As demonstrated here, LAK, and CIK cells possess a high level of cytotoxic activity against tumor cell lines both resistant and sensitive to chemotherapeutic agents such as doxorubicin or vinblastine. CIK cells possessed a higher level of cytotoxic activity than LAK cells as determined by 51Cr release and a tumor colony assay. Monoclonal antibodies against P-glycoprotein did not block the lysis of tumor cells resistant to chemotherapy by CIK cells. In contrast, antibodies to LFA-1 and ICAM-1 blocked CIK cell-mediated tumor cell lysis. These data demonstrate that immunological approaches to cancer therapy may be useful in overcoming disease caused by drug resistance.
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PMID:Sensitivity of multidrug-resistant tumor cell lines to immunologic effector cells. 861 99

Multidrug resistance (MDR) is a phenomenon by which tumor cells exposed to a single anti-proliferative agent acquire resistance to other structurally and functionally unrelated drugs. The classical form of MDR is caused by a plasma-membrane protein currently named P-glycoprotein or P-170 encoded by the human mdr-1 gene in its functional isoform. In vitro cell lines expressing P-170 usually also present phenotypic and functional alterations. In the present study we report that the cytotoxicity mediated by tumor necrosis factor alpha (TNF alpha) in MDR variants of the human T-lymphoblastoid CEM cell line is associated with apoptosis (programmed cell death). Susceptibility of MDR cells to apoptosis was increased upon cycloheximide + TNF alpha sequential treatment, whereby the impairment of protein synthesis due to the former agent was followed by the effect of cytokine exposure. Massive apoptosis of P-170-positive cells, but not of controls, was also obtained by depletion of nutrients (i.e., serum starvation). In contrast, TNF-alpha exerted a similar apoptotic effect in epithelial (MCF-7) or myeloma (S8226) drug-sensitive/ -resistant cell pairs. However, the MDR variant of myeloma S8226 was more sensitive to the cytostatic effect of TNF alpha than the parental drug-sensitive cell line. These results suggest that the presence of the MDR phenotype may be associated with increased histotype-dependent cell susceptibility to specific, protein-synthesis-independent, apoptotic pathways.
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PMID:Tumor necrosis factor alpha is a powerful apoptotic inducer in lymphoid leukemic cells expressing the P-170 glycoprotein. 876 May 94

The effects that TNF-alpha exerts on Friend erythroleukemia (FLC) and on one multidrug resistant variant (FLC-DXR) of the cell line were studied. Resistance to doxorubicin of FLC-DXR entails two mechanisms: overexpression of P-glycoprotein; and increased glutathione-related activities. Both these might also decrease the effects of the cytokine. Nonetheless, TNF caused even greater cytotoxicity and apoptosis, with no induction of differentiation markers, in FLC-DXR. In addition, TNF produced minor changes of the levels of reduced and oxidized glutathione in the cell lines, and its cytotoxic effects were not inluenced by agents that modify the cell glutathione content such as buthionine sulfoximine, ethacrynic acid, or N-acetyl cysteine. We can exclude that the mechanisms of drug resistance of FLC-DXR prevent the response to the cytokine.
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PMID:TNF-induced apoptosis in multidrug resistant friend erythroleukemia is not influenced by the P-glycoprotein and glutathione status of the cell line. 886 68

Reversal of multidrug resistance (MDR) may offer a means of increasing the effectiveness of tumour chemotherapy. A variety of recent evidence indicates that cytokines may be particularly useful in this endeavour. To investigate the molecular mechanism by which cytokines may sensitise multidrug-resistant colon carcinoma cells, HCT15 and HCT116, to treatment with MDR-related drugs, we evaluated the effects of the human cytokines tumour necrosis factor alpha (TNF alpha), interleukin 2 (IL-2) and interferon gamma (IFN gamma) on mdr1 gene expression at the mRNA level by reverse transcription-polymerase chain reaction (RT-PCR) and at the protein level with monoclonal antibodies by immuno flow cytometry. P-glycoprotein function was examined after accumulation of the fluorescent drug, doxorubicin, by flow cytometry. Chemosensitivity to doxorubicin and vincristine was analysed using the XTT assay. All three cytokines were found to modulate the MDR characteristics on mdr1 expression levels, P-glycoprotein function and measured chemosensitivity to MDR-associated anti-cancer drugs. This cytokine-induced reversal of MDR was strongly time dependent, with maximal effects after 48 and 72 h of cytokine treatment. If similar modulation of MDR phenotype can be obtained in in vivo models, it may be possible to verify the time course for modulation by cytokine treatment and to design appropriate clinical trials of this strategy for MDR reversal.
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PMID:Modulation of mdr1 expression by cytokines in human colon carcinoma cells: an approach for reversal of multidrug resistance. 891 33

In the central nervous system the blood-brain and blood-retinal barriers (BBB and BRB respectively) are instrumental in maintaining homeostasis of the neural parenchyma and controlling leucocyte traffic. These cellular barriers are formed primarily by the vascular endothelium of the brain and retina although in the latter the pigmented epithelial cells also form part of the barrier. From primary cultures of rat brain endothelium, retinal endothelium and retinal pigment epithelium (RPE) we have generated temperature sensitive SV40 large T immortalised cell lines. Clones of brain (GP8.3) and retinal (JG2.1) endothelia and RPE (LD7.4) have been derived from parent lines that express the large T antigen at the permissive temperature. The endothelial cell (EC) lines expressed P-glycoprotein, GLUT-1, the transferrin receptor, von Willebrand factor and the RECA-1 antigen and exhibited high affinity uptake of acetylated LDL and stained positive with the lectin Griffonia simplicifolia. The RPE cell line was positive for cytokeratins and for the rat RPE antigen RET-PE2. All the cell lines expressed major histocompatibility complex (MHC) class 1 and intercellular adhesion molecule (ICAM)-1 constitutively and could be induced to express MHC class II and vascular cell adhesion molecule (VCAM)-1 following cytokine activation. The EC also expressed platelet endothelial cell adhesion molecule (PECAM)-1. Monolayers of these cells could support the migration of antigen-specific T cell lines. The generation of immortalised cell lines derived from the rat BBB and BRB should prove to be useful tools for the study of these specialised cellular barriers.
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PMID:SV40 large T immortalised cell lines of the rat blood-brain and blood-retinal barriers retain their phenotypic and immunological characteristics. 898 3

We have shown previously that the mouse CD4 memory cell subset can be divided into two subpopulations based on differential expression of P-glycoprotein. Cells with high levels of P-glycoprotein can be detected by extrusion of the fluorochrome Rhodamine 123; they are referred to as R123lo cells. These R123lo T cells increase with age and have been shown not to respond to anti-CD3 and IL-2 by proliferation or IL-4 production. We report here (a) that the failure of the R123lo CD4 memory population to respond to anti-CD3/IL-2 stimulation cannot be overcome by addition of anti-CD28, PMA, IL-4 or IL-12, alone or in various combinations, and (b) that this age-dependent subset exhibits impaired production of IL-5 and IL-10 as well as decreased proliferation. R123lo CD4 memory cells from young mice are also deficient in IFN gamma secretion by this subset. Although the R123lo cells respond poorly to receptor-dependent agonists, they can be triggered to proliferate and produce IFN gamma by the combination of PMA and ionomycin. In addition to increasing the proportion of R123lo cells in the memory CD4 pool, aging also leads to a decline in the ability of R123hi cells to produce IL-5 and IL-10. Thus, the accumulation of R123lo cells cannot by itself account for the poor proliferation and Th2 cytokine production of aged T cells in cytokine-supplemented culture conditions.
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PMID:Cytokine production by subsets of CD4 memory T cells differing in P-glycoprotein expression: effects of aging. 915 47


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