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)

Murine double minute 2 (MDM2) negatively regulates the activity of the tumor suppressor protein p53. Nutlin-3 is a MDM2 inhibitor under preclinical investigation as nongenotoxic activator of the p53 pathway for cancer therapy. Here, nutlin-3 was evaluated for its activity alone or in combination with established chemotherapeutic drugs for antitumor action in chemosensitive and chemoresistant neuroblastoma and rhabdomyosarcoma cell lines. Effects of nutlin-3 single treatment were much more pronounced in p53 wild-type cell lines (IC(50)s <3 micromol/L) than in p53-mutated cell lines (IC(50)s >17 micromol/L). In sharp contrast to the expectations, nutlin-3 concentrations that did not affect viability of p53-mutated cell lines strongly increased the efficacy of vincristine in p53-mutated, P-glycoprotein (P-gp)-overexpressing cell lines (decrease in IC(50)s 92- to 3,434-fold). Similar results were obtained for other P-gp substrates. Moreover, nutlin-3 reduced efflux of rhodamine 123 and other fluorescence dyes that are effluxed by P-gp. Investigation of Madin-Darby canine kidney (MDCK) II cells stably transfected with plasmids encoding for P-gp (MDCKII MDR1) or multidrug resistance protein 1 (MRP-1, MDCKII MRP1) revealed that nutlin-3 not only interferes with P-gp but also affects MRP-1-mediated efflux. Kinetic studies and investigation of P-gp-ATPase activity showed that nutlin-3 is likely to act as a P-gp transport substrate. Examination of the nutlin-3 enantiomers nutlin-3a and nutlin-3b revealed that, in contrast to MDM2-inhibitory activity that is limited to nutlin-3a, both enantiomers similarly interfere with P-gp-mediated drug efflux. In conclusion, nutlin-3-induced inhibition of P-gp and MRP-1 was discovered as a novel anticancer mechanism of the substance in this report.
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PMID:Reversal of P-glycoprotein-mediated multidrug resistance by the murine double minute 2 antagonist nutlin-3. 1914 53

The multidrug resistance protein 1 (MDR1 or ABCB1) gene encodes a P-glycoprotein that protects the brain against neurotoxicants. Certain MDR1 genetic variants are known to compromise the function of this transporter and may thus be associated with Parkinson disease (PD). We therefore conducted a large case-control study investigating the potential relationship between MDR1 variants and PD. We determined the frequency of three MDR1 variants in 599 European PD patients and controls and further stratified the population by ethnicity, age at onset, and exposure to pesticides. We detected no relevant association in either the entire sample, or when separately investigating by ethnic origin or age at onset. However, the distribution of c.3435C/T differed significantly between PD patients exposed to pesticides compared to those non-exposed (odds ratio=4.74; confidence interval=[1.009; 22.306]); p=0.047), suggesting that common MDR1 variants might influence the risk to develop PD in conjunction with exposure to pesticides.
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PMID:MDR1 variants and risk of Parkinson disease. Association with pesticide exposure? 1918 62

Sunitinib is an ATP-competitive multi-targeted tyrosine kinase inhibitor. In this study, we evaluated the possible interaction of sunitinib with P-glycoprotein (P-gp, ABCB1), multidrug resistance protein 1 (MRP1, ABCC1), breast cancer resistance protein (BCRP, ABCG2) and lung-resistance protein (LRP) in vitro. Our results showed that sunitinib completely reverse drug resistance mediated by ABCG2 at a non-toxic concentration of 2.5muM and has no significant reversal effect on ABCB1-, ABCC1- and LRP-mediated drug resistance, although a small synergetic effect was observed in combining sunitinib and conventional chemotherapeutic agents in ABCB1 overexpressing MCF-7/adr and parental sensitive MCF-7 cells, ABCC1 overexpressing C-A120 and parental sensitive KB-3-1 cells. Sunitinib significantly increased intracellular accumulation of rhodamine 123 and doxorubicin and remarkably inhibited the efflux of rhodamine 123 and methotrexate by ABCG2 in ABCG2-overexpressing cells, and also profoundly inhibited the transport of [(3)H]-methotrexate by ABCG2. However, sunitinib did not affect the expression of ABCG2 at mRNA or protein levels. In addition, sunitinib did not block the phosphorylation of Akt and Erk1/2 in ABCG2-overexpressing or parental sensitive cells. Overall, we conclude that sunitinib reverses ABCG2-mediated MDR through inhibiting the drug efflux function of ABCG2. These findings may be useful for cancer combinational therapy with sunitinib in the clinic.
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PMID:Sensitization of ABCG2-overexpressing cells to conventional chemotherapeutic agent by sunitinib was associated with inhibiting the function of ABCG2. 1923 21

The effects of 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] on gene expression and function were studied in Caco-2 cells. Microarray analyses, real-time quantitative polymerase chain reactions, and Western blotting were used to determine the mRNA and protein expression of transporters and enzymes after 1,25(OH)(2)D(3) or vehicle (0.1% ethanol) treatment for 1, 3, 6, and 10 days. The mRNA and protein expressions of the apical sodium-dependent bile acid transporter, oligopeptide transporter 1, multidrug resistance-associated protein (MRP) 3, and sulfotransferase 1E1 remained unchanged with 1,25(OH)(2)D(3) treatment, whereas those for CYP3A4, multidrug resistance protein 1, and MRP2 were significantly increased (P < 0.05). 1,25(OH)(2)D(3) treatment significantly enhanced MRP4 protein expression by increasing protein stability without affecting mRNA expression, as confirmed in cycloheximide experiments. Marked increase in 6beta-hydroxylation of testosterone by CYP3A4 was also observed in the 6-day 1,25(OH)(2)D(3)-treated (100 nM) cell lysate. The transport of [(3)H]digoxin, the P-glycoprotein (P-gp) substrate, after treatment with 100 nM 1,25(OH)(2)D(3) for 3 days revealed a higher apparent permeability (P(app)) value in the basal (B)-to-apical (A) direction over that of vehicle treatment (15.1 +/- 0.53 x 10(-6) versus 11.8 +/- 0.58 x 10(-6) cm/s; P < 0.05), whereas the P(app) in the A-to-B direction was unchanged; the efflux ratio was increased (from 5.8 to 8.0). Reduced cellular retention of 5-(and-6)-carboxy-2',7'-dichlorofluorescein, suggestive of higher MRP2 activity, was observed in the 3-day 100 nM 1,25(OH)(2)D(3)-treated cells over controls. Higher protein expression of CYP3A4, MRP2, P-gp, and MRP4 was also observed after a 6-day treatment with other vitamin D analogs (100 nM 1alpha-hydroxyvitamin D(3),1alpha-hydroxyvitamin D(2) or Hectorol, and 25-hydroxyvitamin D(3)) in Caco-2 cells, suggesting a role of 1,25(OH)(2)D(3) and analogs in the activation of enzymes and transporters via the vitamin D receptor.
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PMID:Up-regulation of transporters and enzymes by the vitamin D receptor ligands, 1alpha,25-dihydroxyvitamin D3 and vitamin D analogs, in the Caco-2 cell monolayer. 1941 24

In the present study, the ability of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), also known as statins, to regulate the gene expression and function of multidrug resistance protein 1 (MDR1/P-glycoprotein) and differences between their acid and lactone forms were examined in human intestinal epithelial LS180 cells. Some statins had the potential to induce the expression of mRNAs for MDR1 and/or CYP3A in either form. The change in the mRNA expression of MDR1 was accompanied by a change in the CsA-dependent intracellular accumulation of rhodamine 123. Simvastatin lactone, but not the acid form, exhibited a strong inductive effect on the mRNA expression of MDR1 and CYP3A in a dose-dependent manner. Sulforaphane significantly suppressed the expression of MDR1 and CYP3A mRNAs induced by atorvastatin lactone, lovastatin acid, and lovastatin lactone, comparable to the control level, and moderately inhibited that by cerivastatin acid, fluvastatin acid and simvastatin lactone. In the case of pitavastatin acid, sulforaphane had no significant effect on the expression of MDR1 mRNA.These results suggested that some statins could induce MDR1 and CYP3A gene expression and these inductive effects differed between the lactone and active hydroxy acid forms, and that PXR-mediated regulation was rarely associated with the mRNA inducibility by pitavastatin acid, unlike that by other statins.
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PMID:Effects of acid and lactone forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on the induction of MDR1 expression and function in LS180 cells. 1942 19

The effects of dietary antioxidative and chemopreventive rosemary phytochemicals on the function of the human drug efflux transporter P-glycoprotein (MDR1, ABCB1) and multidrug resistance protein 1 (MRP1, ABCC1) were investigated using P-glycoprotein-overexpressing human carcinoma KB-C2 cells and human MRP1 gene-transfected KB/MRP cells. The effects of natural phytochemicals found in rosemary such as carnosic acid, carnosol, rosmarinic acid, and ursolic acid were investigated. The accumulation of daunorubicin or rhodamine 123, fluorescent substrates of P-glycoprotein, in KB-C2 cells increased in the presence of carnosic acid, carnosol, and ursolic acid in a concentration-dependent manner. In contrast, carnosic acid, carnosol, rosmarinic acid, and ursolic acid had no effects on the accumulation of calcein, a fluorescent substrate of MRP1, in KB/MRP cells. The ATPase activities of P-glycoprotein were stimulated by carnosic acid, carnosol, and ursolic acid. KB-C2 cells were sensitized to vinblastine cytotoxicity by carnosic acid, showing that carnosic acid reverses multidrug resistance. These results suggest that rosemary phytochemicals, such as carnosic acid, have inhibitory effects on anticancer drug efflux transporter P-glycoprotein and may become useful to enhance the efficacy of cancer chemotherapy.
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PMID:Inhibition of anticancer drug efflux transporter P-glycoprotein by rosemary phytochemicals. 1994 62

Pharmacotherapy of brain HIV-1 infection may be limited by ABC transporters [i.e., P-glycoprotein (P-gp), multidrug resistance protein 1 (Mrp1)] that export antiretroviral drugs from HIV-1 brain cellular targets (i.e., astrocytes, microglia). Using an in vitro astrocyte model of an HIV-1 associated inflammatory response, our laboratory has shown that cytokines [i.e., tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1 beta, IL-6], which are secreted in response to HIV-1 envelope glycoprotein gp120 exposure, can decrease P-gp functional expression; however, it is unknown whether these same cytokines can alter expression and/or activity of other ABC transporters (i.e., Mrp1). In primary cultures of rat astrocytes, Mrp1 expression was increased by TNF-alpha (2.7-fold) but was not altered by IL-1 beta or IL-6. Cellular retention of 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, an Mrp substrate, was reduced in TNF-alpha-treated astrocytes, suggesting increased Mrp-mediated transport. Pharmacologic inhibition of nuclear factor-kappaB (NF-kappaB) signaling with SN50 prevented both TNF-alpha release and Mrp1 expression changes in astrocytes triggered with gp120; however, SN50 did not attenuate Mrp1 expression in cells triggered with TNF-alpha. In contrast, Mrp1 functional expression was not altered in the presence of gp120 or TNF-alpha when astrocyte cultures were pretreated with 1,9-pyrazoloanthrone (SP600125), an established c-Jun N-terminal kinase (JNK) inhibitor. SP600125 did not affect TNF-alpha release from cultured astrocytes triggered with gp120. Mrp1 mRNA expression was increased after treatment with gp120 (1.6-fold) or TNF-alpha (1.7-fold), suggesting altered Mrp1 gene transcription. These data suggest that gp120 and TNF-alpha can up-regulate Mrp1 expression in cultured astrocytes. Furthermore, our results imply that both NF-kappaB and JNK signaling are involved in Mrp1 regulation during an HIV-1 associated inflammatory response.
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PMID:Regulation of multidrug resistance protein 1 by tumor necrosis factor alpha in cultured glial cells: involvement of nuclear factor-kappaB and c-Jun N-terminal kinase signaling pathways. 2005 32

[(11)C]N-desmethyl-Loperamide ([(11)C]dLop) is used in positron emission tomography (PET) to measure the in vivo activity of efflux transporters that block the passage of drugs across the blood-brain barrier. The three most prevalent ATP-binding cassette efflux transporters at the blood-brain barrier are P-glycoprotein (P-gp), multidrug resistance protein 1 (Mrp1), and breast cancer resistance protein (BCRP). We sought to measure the selectivity of dLop among these three transporters. The selectivity of dLop at low concentrations (< or =1 nM) was measured both as the accumulation of [(3)H]dLop in human cells that overexpress each transporter and as the uptake of [(11)C]dLop in brains of mice that lack genes encoding P-gp, Mrp1, or BCRP. The selectivity of dLop at high concentrations (> or =20 microM) was measured as the inhibition of uptake of a fluorescent substrate and the change in cytotoxicity of drugs effluxed at each transporter. Accumulation of [(3)H]dLop was lowest in cells overexpressing P-gp, and the uptake of [(11)C]dLop was highest in brains of mice lacking P-gp. At high concentrations, dLop selectively inhibited P-gp function and also decreased the resistance of only the P-gp-expressing cells to cytotoxic agents. dLop is selective for P-gp among these three transporters, but its activity is dependent on concentration. At low concentrations (< or =1 nM), dLop acts only as a substrate; at high concentrations (> or =20 microM), it acts as both a substrate and an inhibitor (i.e., a competitive substrate). Because low concentrations of radiotracer are used for PET imaging, [(11)C]dLop acts selectively and only as a substrate for P-gp.
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PMID:N-desmethyl-loperamide is selective for P-glycoprotein among three ATP-binding cassette transporters at the blood-brain barrier. 2021 14

Apatinib, a small-molecule multitargeted tyrosine kinase inhibitor, is in phase III clinical trial for the treatment of patients with non-small-cell lung cancer and gastric cancer in China. In this study, we determined the effect of apatinib on the interaction of specific antineoplastic compounds with P-glycoprotein (ABCB1), multidrug resistance protein 1 (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2). Our results showed that apatinib significantly enhanced the cytotoxicity of ABCB1 or ABCG2 substrate drugs in KBv200, MCF-7/adr, and HEK293/ABCB1 cells overexpressing ABCB1 and in S1-M1-80, MCF-7/FLV1000, and HEK293/ABCG2-R2 cells overexpressing ABCG2 (wild-type). In contrast, apatinib did not alter the cytotoxicity of specific substrates in the parental cells and cells overexpressing ABCC1. Apatinib significantly increased the intracellular accumulation of rhodamine 123 and doxorubicin in the multidrug resistance (MDR) cells. Furthermore, apatinib significantly inhibited the photoaffinity labeling of both ABCB1 and ABCG2 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner. The ATPase activity of both ABCB1 and ABCG2 was significantly increased by apatinib. However, apatinib, at a concentration that produced a reversal of MDR, did not significantly alter the ABCB1 or ABCG2 protein or mRNA expression levels or the phosphorylation of AKT and extracellular signal-regulated kinase 1/2 (ERK1/2). Importantly, apatinib significantly enhanced the effect of paclitaxel against the ABCB1-resistant KBv200 cancer cell xenografts in nude mice. In conclusion, apatinib reverses ABCB1- and ABCG2-mediated MDR by inhibiting their transport function, but not by blocking the AKT or ERK1/2 pathway or downregulating ABCB1 or ABCG2 expression. Apatinib may be useful in circumventing MDR to other conventional antineoplastic drugs.
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PMID:Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters. 2087 99

The magnitude of P-glycoprotein [(P-gp)/multidrug resistance protein 1 (MDR1)]-mediated drug-drug interaction (DDI) at the blood-brain barrier (BBB) in rats was estimated by in vitro-in vivo correlation (IVIVC). In in vitro studies, rat Mdr1a-expressing LLC-PK1 cells were examined for the evaluation of P-gp inhibitory activity using digoxin as a P-gp probe substrate. The in vitro K(i) value was calculated using a modified corrected flux ratio that reflects the P-gp function. In in vivo studies, digoxin with or without P-gp inhibitors was administered to rats by constant intravenous infusion to evaluate the effect of P-gp inhibition on digoxin transport to the brain under steady-state conditions. In the presence of elacridar, the brain-to-plasma concentration ratio (K(p,brain)) of digoxin was approximately 14 times the control value. However, no significant change in the K(p,brain) was observed in the presence of clinically used P-gp inhibitors, with the exception of cyclosporine A. A positive correlation was found between the in vivo K(p,brain) of digoxin and [I(,unbound)/K(i)] (where I(,unbound) is the unbound plasma concentration of P-gp inhibitors). Compounds with [I(,unbound)/K(i)] values of >1 increased K(p,brain) of digoxin in rats. In summary, we used a quantitative approach to evaluate the impact of P-gp-mediated DDI at the rat BBB. We successfully established the IVIVC, which indicated the potential DDI in the presence of potent P-gp inhibitors. On the basis of the IVIVC in rats and K(i) values in human MDR1, we speculated that clinically used P-gp inhibitors do not cause DDI at the human BBB, because none of the compounds studied showed [I(,unbound)/K(i)] values of >1 at therapeutic doses.
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PMID:Quantitative investigation of the impact of P-glycoprotein inhibition on drug transport across blood-brain barrier in rats. 2096 62


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