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)

P-Glycoprotein is a cell membrane-associated protein that transports a variety of exogenous (including drugs) and endogenous substances. P-Glycoprotein may also be involved in transmembrane transport of some endogenous proteins; thus, it may have physiological function in cytokine transport. Previous studies suggested that P-glycoprotein expression is genetically determined. The aim of this study was to examine involvement of multidrug resistance gene (MDR1) C3435T and G2677T polymorphisms in release of cytokines from phythemaglutynin (PHA)-stimulated peripheral blood mononuclear cells, as well as treated with methotrexate or dexamethasone. The release of cytokines: interleukin-2 (IL-2), IL-4, IL-6, IL-10, interferon-gamma (INF-gamma) and tumor necrosis factor-alpha (TNF-alpha) was determined in supernatants of mononuclear cell cultures from 72 healthy subjects, measured by flow cytometry. The release of INF-gamma, IL-2, IL-4 and TNF-alpha in cultures from subjects with 2677(T-T) 3435(T-T) haplotype pair was significantly decreased as compared to subjects with other haplotypes. There were no statistically significant differences in release of IL-6 and IL-10. The results of this study suggest an association between C3435T and G2677T MDR1 polymorphisms and transmembrane transport of some cytokines. Although the studied polymorphisms may be in linkage with polymorphisms of other transporters involved in cytokine release, it seems that the present results indirectly indicate involvement of P-glycoprotein in transport of some cytokines. Moreover, determination of C3435T and G2677T MDR1 polymorphisms might be useful in response prediction to therapy with methotrexate and dexamethasone.
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PMID:Involvement of C3435T and G2677T multidrug resistance gene polymorphisms in release of cytokines from peripheral blood mononuclear cells treated with methotrexate and dexamethasone. 1632 74

In a previous study, we observed that cytokine-induced apoptosis inhibitor 1 (CIAPIN1), a newly identified apoptosis inhibitor, was upregulated at the mRNA level in a multidrug-resistant gastric cancer cell line SGC7901/VCR. The aim of this study was to explore the role of CIAPIN1 in the development of multidrug resistance (MDR) in gastric cancer cells. Upregulation of CIAPIN1 in MDR gastric cancer cells was confirmed by semiquantitative RT-PCR and Western blotting. Using cDNA transfection and RNA interference, we successfully established stable transfectants with upregulation (i.e., SGC7901-pCIAPIN1) or downregulation (i.e., SGC7901-pSiCIAPIN1 and SGC7901/ADR-pSiCIAPIN1) of CIAPIN1 expression, respectively. In vitro drug sensitivity assay demonstrated that overexpression of CIAPIN1 conferred MDR in SGC7901 cells whereas downregulation of CIAPIN1 sensitized SGC7901 and SGC7901/ADR cells to anticancer drugs. CIAPIN1 protected both SGC7901 and SGC7901/ADR cells from ADR-induced apoptosis and reduced intracellular accumulation and retention of adriamycin. Moreover, expression of P-glycoprotein (P-gp or MDR-1, a product of MDR-1 gene) and MDR-related protein-1 (MRP-1) was upregulated by CIAPIN1. In addition, Western blotting revealed that CIAPIN1 decreased the expression of Bcl-2, Bax and p53. Therefore, it is concluded that CIAPIN1 confers MDR in gastric cancer cells, likely by upregulating MDR-1 and MRP-1.
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PMID:CIAPIN1 confers multidrug resistance by upregulating the expression of MDR-1 and MRP-1 in gastric cancer cells. 1641 Jul 21

The death-inducing cytokine TRAIL is a promising agent for anticancer therapy since it preferentially kills cancer versus normal cells; however, some cancer cells are TRAIL-resistant. We initially explored whether overexpression of the MDR1 gene product P-glycoprotein (P-gp), which causes multidrug resistance (MDR) in cancer cells, also contributes to TRAIL-resistance. Surprisingly, our results revealed that P-gp-overexpression enhances TRAIL-induced apoptosis not only in neoplastic cells transfected with the MDR1 gene but also in MDR variants selected with cytotoxic anticancer agents. Mechanistic analysis of TRAIL-induced apoptosis in the MDR1-transfected MCF-7 breast cancer cell line BC-19 revealed that TRAIL-triggered significantly more apoptosis in these cells compared with parental MCF-7 cells by binding to the TRAIL receptor DR5. DR5 but not DR4 engagement by TRAIL attenuated cellular ATP levels by robustly stimulating P-gp ATPase activity, and thus triggered P-gp-dependent apoptosis by depletion of the cellular ATP pool. In addition to hyperactive P-gp-mediated ATP hydrolysis, TRAIL-induced, P-gp-potentiated apoptosis was associated with activation of caspases-6, -7, -8, and -9; Bid cleavage; and mitochondrial depolarization. P-gp interacted with the TRAIL receptors DR4, DR5, and DcR1 in plasma membranes and enhanced TRAIL binding to DR5. Interestingly, the decreased level of the decoy TRAIL receptor, DcR1, in BC-19 cells further sensitized these cells to TRAIL. Therefore, both extrinsic and intrinsic apoptosis pathways are involved in this process. These findings for the first time reveal that TRAIL treatment preferentially causes apoptosis in P-gp-overexpressing MDR cells, and suggests significant clinical implications for the use of TRAIL in treating neoplasms that have failed chemotherapy.
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PMID:P-glycoprotein enhances TRAIL-triggered apoptosis in multidrug resistant cancer cells by interacting with the death receptor DR5. 1675 35

In this work, we examined the ability of gp120, a human immunodeficiency virus-1 (HIV-1) viral envelope glycoprotein, to trigger the innate immune response in astrocytes, an HIV-1 brain cellular target, and we investigated the functional expression of the ATP-binding cassette membrane transporter P-glycoprotein (P-gp) in primary cultures of rat astrocytes treated with gp120 or cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6]. Standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium and d-mannitol uptake assays confirmed that HIV-1(96ZM651) gp120 treatment did not alter cell viability or membrane permeability. Semiquantitative reverse-transcriptase polymerase chain reaction analysis and enzyme-linked immunosorbent assay demonstrated increased TNF-alpha, IL-1beta, and IL-6 mRNA and protein expression in cultures treated with HIV-1(96ZM651) gp120, suggesting in vitro activation of immune responses. Cytokine secretion was detected when CXCR4 but not CCR5 was inhibited with a specific antibody, implying that cytokine secretion is primarily mediated via CCR5 in astrocytes triggered with HIV-1(96ZM651) gp120. P-gp protein expression was increased in astrocyte cultures exposed to TNF-alpha (2.9-fold) or IL-1beta (1.6-fold) but was decreased profoundly in the presence of IL-6 (8.9-fold), suggesting that IL-6 is primarily involved in modulating P-gp expression. In parallel, after HIV-1(96ZM651) gp120 treatment, immunoblotting analysis showed a significant decrease in P-gp expression (4.7-fold). Furthermore, the accumulation of two P-gp substrates, digoxin and saquinavir (an HIV-1 protease inhibitor), was enhanced (1.5- to 1.8-fold) in HIV-1(96ZM651) gp120-treated astrocyte monolayers but was not altered by P-gp inhibitors [e.g., valspodar (PSC833) and elacridar (GF120918)], suggesting a loss of transport activity. Taken together, these data imply that HIV-1(96ZM651) gp120 or cytokine treatment modulate P-gp functional expression in astrocytes, which may lead to complex drug-transporter interactions during HIV-1 encephalitis-associated immune responses.
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PMID:HIV-1 viral envelope glycoprotein gp120 triggers an inflammatory response in cultured rat astrocytes and regulates the functional expression of P-glycoprotein. 1679 May 32

Dose-limiting diarrhea and myelosuppression compromise the success of irinotecan (7-ethyl-10-[4-[1-piperidino]-1-piperidino]carbonyloxycamptothecin) (CPT-11)-based chemotherapy. A recent pilot study indicates that thalidomide attenuates the toxicity of CPT-11 in cancer patients. This study aimed to investigate whether coadministered thalidomide modulated the toxicities of CPT-11 and the underlying mechanisms using several in vivo and in vitro models. Diarrhea, intestinal lesions, cytokine expression, and intestinal epithelial apoptosis were monitored. Coadministered thalidomide (100 mg/kg i.p. for 8 days) significantly attenuated body weight loss, myelosuppression, diarrhea, and intestinal histological lesions caused by CPT-11 (60 mg/kg i.v. for 4 days). This was accompanied by inhibition of tumor necrosis factor-alpha, interleukins 1 and 6 and interferon-gamma, and intestinal epithelial apoptosis. Coadministered thalidomide also significantly increased the systemic exposure of CPT-11 but decreased that of SN-38 (7-ethyl-10-hydroxycampothecin). It significantly reduced the biliary excretion and cecal exposure of CPT-11, SN-38, and SN-38 glucuronide. Thalidomide hydrolytic products inhibited hydrolysis of CPT-11 in rat liver microsomes but not in primary rat hepatocytes. In addition, thalidomide and its major hydrolytic products, such as phthaloyl glutamic acid (PGA), increased the intracellular accumulation of CPT-11 and SN-38 in primary rat hepatocytes. They also significantly decreased the transport of CPT-11 and SN-38 in Caco-2 and parental MDCKII cells. Thalidomide and PGA also significantly inhibited P-glycoprotein (PgP/MDR1), multidrug resistance-associated protein (MRP1)- and MRP2-mediated CPT-11 and SN-38 transport in MDCKII cells. These results provide insights into the pharmacodynamic and pharmacokinetic mechanisms for the protective effects of thalidomide against CPT-11-induced intestinal toxicity.
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PMID:A mechanistic study on reduced toxicity of irinotecan by coadministered thalidomide, a tumor necrosis factor-alpha inhibitor. 1681 71

P-glycoprotein, encoded by the multidrug resistance (MDR)-1 gene, expels various drugs from cells resulting in multidrug resistance. We found previously that interleukin-2, a lymphocyte-activation cytokine, induces P-glycoprotein expression on lymphocytes. Lymphocyte activation involves adhesion with the extracellular matrix, such as hyaluronan, through adhesion molecules on lymphocytes. We investigated the transcriptional regulation of MDR-1 in lymphocytes by fragmented hyaluronan. Fragmented hyaluronan (especially the 6.9-kDa form), not native high molecular hyaluronan, induced translocation of YB-1, a specific transcriptional factor for MDR-1, from the cytoplasm into the nucleus and resulted in the transcription of MDR-1 and the expression of P-glycoprotein on lymphocytes in a dose-dependent manner. Transfection of YB-1 antisense oligonucleotides inhibited P-glycoprotein expression induced by fragmented hyaluronan. The fragmented hyaluronan induced significant P-glycoprotein expression on only activated CD4+ T cells, which highly expressed CD69, and resulted in excretion of intracellular dexamethasone added in vitro. Cyclosporin A, a competitive P-glycoprotein inhibitor, restored intracellular dexamethasone levels in CD4+ T cells. Anti-CD44 monoclonal antibody (Hermes-1) inhibited fragmented hyaluronan-induced YB-1 activation and P-glycoprotein expression in CD4+ T cells. We provide the first evidence that binding of fragmented hyaluronan to CD44 induces YB-1 activation followed by P-glycoprotein expression in accordance with activation of CD4+ T cells. Our findings imply that CD4+ T cell activation by fragmented hyaluronan, induced by characteristic extracellular matrix changes in inflammation, tumors, and other conditions, results in P-glycoprotein-mediated multidrug resistance.
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PMID:Fragmented hyaluronan induces transcriptional up-regulation of the multidrug resistance-1 gene in CD4+ T cells. 1703 19

We investigated the role of cytokine-induced apoptosis inhibitor 1 (CIAPIN1), a newly identified apoptosis inhibitor, in leukemia cell multidrug resistance (MDR) and its possible underlying mechanisms. CIAPIN1 was found to be overexpressed at the mRNA and protein levels in the vincristine-induced multidrug-resistant leukemia cell line HL-60/VCR, compared with HL-60, its parental cell line. In this study, we transfected HL-60 with a eukaryotic expression vector of CIAPIN1. In vitro drug sensitivity assays suggested that HL-60-CIAPIN1 cells conferred resistance to both P-glycoprotein (P-gp)-related and -unrelated drugs. Blocking CIAPIN1 expression in HL-60/VCR cells by CIAPIN1-specific small interfering RNA increased the cells' sensitivity to various chemotherapeutic drugs. Flow cytometry results suggested that CIAPIN1 expression could suppress adriamycin-induced apoptosis, accompanied by a decreased accumulation and increased release of adriamycin. Semiquantitative RT-PCR, Western blot analysis, and luciferase reporter assays suggested that CIAPIN1 could significantly upregulate the expression of MDR-1 and Bcl-2, the transcription of the MDR-1 gene, as well as downregulate the expression of Bax. Additionally, the inhibition of CIAPIN1 expression by RNA interference or P-gp inhibitor could partially reverse CIAPIN1-mediated MDR. Taken together, our findings suggest that downregulating CIAPIN1 could sensitize leukemia cells to chemotherapeutic drugs by downregulating MDR-1 and Bcl-2 and by upregulating Bax, yet not altering either glutathione-S-transferase activity or intracellular glutathione content in leukemia cells. Further study of CIAPIN1's function may reveal more of the mechanisms of leukemia MDR and result in the development of strategies to treat leukemia.
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PMID:A new apoptosis inhibitor, CIAPIN1 (cytokine-induced apoptosis inhibitor 1), mediates multidrug resistance in leukemia cells by regulating MDR-1, Bcl-2, and Bax. 1805 32

Here, we report that diesel exhaust particles (DEPs), a major constituent of urban air pollution, affect blood-brain barrier function at the tissue, cellular, and molecular levels. Isolated rat brain capillaries exposed to DEPs showed increased expression and transport activity of the key drug efflux transporter, P-glycoprotein (6 h EC(50) was approximately 5 microg/ml). Up-regulation of P-glycoprotein was abolished by blocking transcription or protein synthesis. Inhibition of NADPH oxidase or pretreatment of capillaries with radical scavengers ameliorated DEP-induced P-glycoprotein up-regulation, indicating a role for reactive oxygen species in signaling. DEP exposure also increased brain capillary tumor necrosis factor-alpha (TNF-alpha) levels. DEP-induced P-glycoprotein up-regulation was abolished when TNF-receptor 1 (TNF-R1) was blocked and was not evident in experiments with capillaries from TNF-R1 knockout mice. Inhibition of JNK, but not NF-kappaB, blocked DEP-induced P-glycoprotein up-regulation, indicating a role for AP-1 in the signaling pathway. Consistent with this, DEPs increased phosphorylation of c-jun. Together, our results show for the first time that a component of air pollution, DEPs, alters blood-brain barrier function through oxidative stress and proinflammatory cytokine production. These experiments disclose a novel blood-brain barrier signaling pathway, with clear implications for environmental toxicology, CNS pathology, and the pharmacotherapy of CNS disorders.
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PMID:Diesel exhaust particles induce oxidative stress, proinflammatory signaling, and P-glycoprotein up-regulation at the blood-brain barrier. 1847 46

Pharmacotherapy of central nervous system (CNS) disorders (e.g., neurodegenerative diseases, epilepsy, brain cancer, and neuro-AIDS) is limited by the blood-brain barrier. P-glycoprotein, an ATP-driven, drug efflux transporter, is a critical element of that barrier. High level of expression, luminal membrane location, multispecificity, and high transport potency make P-glycoprotein a selective gatekeeper of the blood-brain barrier and thus a primary obstacle to drug delivery into the brain. As such, P-glycoprotein limits entry into the CNS for a large number of prescribed drugs, contributes to the poor success rate of CNS drug candidates, and probably contributes to patient-to-patient variability in response to CNS pharmacotherapy. Modulating P-glycoprotein could therefore improve drug delivery into the brain. Here we review the current understanding of signaling mechanisms responsible for the modulation of P-glycoprotein activity/expression at the blood-brain barrier with an emphasis on recent studies from our laboratories. Using intact brain capillaries from rats and mice, we have identified multiple extracellular and intracellular signals that regulate this transporter; several signaling pathways have been mapped. Three pathways are triggered by elements of the brain's innate immune response, one by glutamate, one by xenobiotic-nuclear receptor (pregnane X receptor) interactions, and one by elevated beta-amyloid levels. Signaling is complex, with several pathways sharing common signaling elements [tumor necrosis factor (TNF) receptor 1, endothelin (ET) B receptor, protein kinase C, and nitric-oxide synthase), suggesting a regulatory network. Several pathways include autocrine/paracrine elements, involving release of the proinflammatory cytokine, TNF-alpha, and the polypeptide hormone, ET-1. Finally, several steps in signaling are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the clinic.
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PMID:Modulation of P-glycoprotein at the blood-brain barrier: opportunities to improve central nervous system pharmacotherapy. 1856 12

The occurrence of the multidrug resistance phenotype still represents a limiting factor for successful cancer chemotherapy. Numerous efforts have been made to develop strategies for reversal and/or modulation of this major therapy obstacle through targeting at different levels of intervention. The phenomenon of MDR is often associated with overexpression of resistance-associated genes. Since the classical type of MDR in human cancers is mainly mediated by the P-glycoprotein encoded by the multidrug resistance gene 1, mdr1, the majority of reversal approaches target the expression and/or function of the mdr1 gene/P-glycoprotein. Due to the fact that the multidrug phenotype always represents the net effect of a panel of resistance-associated genes/gene products, other resistance genes, e.g. those encoding the multidrug resistance-associated protein MRP or the lung resistance protein LRP, were included in the studies. Cytokines such as tumor necrosis factor alpha and interleukin-2 have been shown to modulate the MDR phenotype in different experimental settings in vitro and in vivo. Several studies have been performed to evaluate their potential as chemosensitizers of tumor cells in the context of a combined application of MDR-associated anticancer drugs like doxorubicin and vincristine with cytokines. Moreover, the capability of cytokines to modulate the expression of MDR-associated genes was demonstrated, either by external addition or by transduction of the respective cytokine gene. Knowledge of the combination effects of cytokines and cytostatics and its link to their MDR-modulating capacity may contribute to a more efficient and to a more individualized immuno-chemotherapy of human malignancies.
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PMID:Cytokine-mediated reversal of multidrug resistance. 1900 98


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