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)

Darunavir (DRV) is a nonpeptidic protease inhibitor (PI) approved for the treatment of human immunodeficiency virus (HIV) infection. DRV displays potent activity against HIV strains resistant to other available PIs. Coadministration with ritonavir (RTV) improves the oral bioavailability of DRV. Inhibition of cytochrome P450 by RTV has been proposed as a mechanism for enhanced DRV bioavailability. However, interaction of these drugs with intestinal transporters has not been elucidated. This study was performed to explore the involvement of P-glycoprotein in transcellular DRV transport in monolayers of human intestinal Caco-2 and in ABCB1 multidrug resistance 1, (MDR1) gene-transfected renal LLC-PK1 (L-MDR1) cell lines. Transepithelial transport of DRV in Caco-2 cell monolayers was 2-fold greater in the basal-to-apical direction compared to that in the opposite direction. RTV had a significant inhibitory effect on the efflux transport of DRV in Caco-2 cells. The apical-to-basal DRV transport was enhanced by P-glycoprotein inhibitors, cyclosporin A and verapamil, as well as multidrug resistance-related protein (MRP/ABCC) inhibitors, probenecid and MK571. Using the L-MDR1 cell line, basal-to-apical DRV transport was much greater than in the opposite direction. Furthermore, cyclosporin A markedly inhibited the basal-to-apical DRV transport. RTV significantly increased the apical-to-basal transport of DRV in L-MDR1 cells, but reduced transport in the opposite direction. DRV inhibited P-glycoprotein-mediated efflux of calcein-acetoxymethyl ester in L-MDR1 cells with the inhibitory potency of 121 microM. These findings suggest that DRV is a substrate of P-glycoprotein and MRP, most likely MRP2. RTV appeared to inhibit P-glycoprotein, thereby enhancing the absorptive transport of DRV.
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PMID:P-glycoprotein mediates efflux transport of darunavir in human intestinal Caco-2 and ABCB1 gene-transfected renal LLC-PK1 cell lines. 1972 Dec 37

A series of 2-fluoro N(10)-substituted acridone derivatives with varying alkyl side chain length with propyl, butyl substitution, and a tertiary amine group at the terminal end of the alkyl side chain were synthesized and screened against cancer cell lines SW 1573, SW 1573 2R 160 (P-gp substrate) which are non-small lung cancer cell lines, MCF-7, MCF-7/MR (BCRP substrate) are breast cancer cell lines, 2008 WT, 2008MRP1, 2008MRP2, 2008MRP3 are ovarian cancer cell lines, and human embryo kidney cell lines like HEK293, HEK293 MRP4, and HEK293 MRP5i. The propyl-series compounds showed lipophilicity in the range of 1.93 to 4.40 and the butyl series in the range of 2.37 to 4.78. The compounds 4, 7, and 8 showed good cytotoxicity against the 60 human cancer cell line panel of the National Cancer Institute, USA. The compounds 14 and 15 showed a better cytotoxicity in most of the cancer cell lines compared to other compounds tested. The DNA-binding properties of the compounds were evaluated based on their affinity or intercalation with CT-DNA measured with absorption titration. The compound 11 bearing planar tricyclic ring linked with a butyl methylpiperazino side chain showed the highest binding affinity with a binding constant (K(i)) of 10.38 x 10 M(-1). Evaluation of the compounds in cell lines with an overexpression of various multidrug resistance-related protein (MRP), P-glycoprotein (P-gp), or Breast Cancer Resistance Protein (BCRP) showed that all compounds are not substrates for any of these transporters.
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PMID:Synthesis of 2-fluoro N(10)-substituted acridones and their cytotoxicity studies in sensitive and resistant cancer cell lines and their DNA intercalation studies. 1985 33

Fifty-two canine and eighteen feline primary pulmonary carcinomas were evaluated immunohistochemically for the expression of proteins associated with multidrug resistance to anti-cancer drugs. P-glycoprotein (PGP), multidrug resistance-related protein (MRP) and lung resistance-related protein (LRP) expression were frequently observed in neoplastic cells of all carcinoma types, and metallothionein (MT) expression was observed in about half of each carcinoma type. Furthermore, overlapping expression was detected in all positive cases. These results indicate that most canine and feline primary pulmonary carcinomas may have strong multidrug resistance, which is related to the PGP, MRP, LRP or MT expression. It might be difficult to treat canine and feline primary pulmonary carcinomas using anti-cancer drugs because of multidrug resistance.
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PMID:Immunohistochemical detection of proteins associated with multidrug resistance to anti-cancer drugs in canine and feline primary pulmonary carcinoma. 2008 24

Ependymomas are neuroepithelial tumors that arise from the ependymal layer bordering the cerebral ventricles and spinal canal. Intracranial ependymoma represents a major encephalic tumor in children, while spinal ependymoma develops more frequently in adults. To understand the pharmacoresistance that characterizes this tumoral entity, we analyzed the level of expression and localization of three major efflux transport proteins with a multidrug resistance function, P-glycoprotein, multidrug resistance-related protein 1 (MRP1) and breast cancer resistance protein (BCRP), in a series of 25 ependymomas from both children and adults. Real-time-PCR analysis showed that all three genes were expressed in all tumors, with no apparent correlation between the level of expression and either age or tumor grade. The MRP1 transcript was expressed at a significantly higher level in spinal tumors than in intracranial tumors. The expression of the proteins corresponding to these genes was confirmed by Western blot analysis. In an immunohistochemical study, P-glycoprotein and BCRP were shown to be associated with the tumoral vessels, where they presented a luminal localization, a prerequisite for their efflux drug activity into the blood. These data indicate that a biochemical, transporter-dependent blood-tumor barrier may exist in ependymomas, which may reduce the tumoral bioavailability of lipophilic and amphiphilic anticancer drugs.
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PMID:P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) localize in the microvessels forming the blood-tumor barrier in ependymomas. 2040 35

Food contains components that may either increase or decrease the bioavailability of a drug. In particular, it is known that grapefruit juice and St. John's Wort induce drug interactions via an effect on the drug-metabolizing enzyme cytochrome P450 (CYP). However, interactions with membrane transporters, such as P-glycoprotein and multidrug resistance-related protein (MRP), may also influence drug bioavailability. The objective of the present study was to investigate the effects of kaempferol, a flavonoid present in food, on the cytotoxicity of anticancer drugs and the mechanisms of drug resistance in the human glioblastoma cell line T98G. Acute exposure to kaempferol inhibited the efflux of calcein, a substrate of MRP; however, chronic exposure caused no apparent effect on calcein efflux. The cytotoxicity of doxorubicin was not influenced by chronic exposure of cells to kaempferol, although that of cisplatin was significantly reduced. Multidrug resistance is often associated with increased levels of MRP1, glutathione S-transferase (GST) and activity by chronic exposure to kaempferol, although MRP2 protein levels are decreased. Accordingly, we hypothesized that the cytotoxicity of anticancer drugs that conjugate with glutathione and the substrate of MRPs may be influenced by long-term intake of drugs such as kaempferol, which are substrates of MRPs and GST.
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PMID:Effects of kaempferol on the mechanisms of drug resistance in the human glioblastoma cell line T98G. 2050 33

Zosuquidar, which modulates P-glycoprotein (P-gp) with minimal delay of anthracycline clearance, may reverse P-gp-mediated resistance in acute myeloid leukemia without increased toxicity. A total of 449 adults older than 60 years with acute myeloid leukemia or high-risk myelodysplastic syndrome enrolled in a randomized placebo-controlled double-blind trial (Eastern Cooperative Oncology Group 3999). Overall survival was compared between patients receiving conventional-dose cytarabine and daunorubicin and either zosuquidar (550 mg; 212 patients) or placebo (221 patients). Median and 2-year overall survival values were 7.2 months and 20% on zosuquidar and 9.4 months and 23% on placebo, respectively (P = .281). Remission rate was 51.9% on zosuquidar and 48.9% on placebo. All cause mortality to day 42 was not different (zosuquidar 22.2% vs placebo 16.3%; P = .158). In vitro modulation of P-gp activity by zosuquidar and expression of P-gp, multidrug resistance-related protein 1, lung resistance protein, and breast cancer resistance protein, were comparable in the 2 arms. Poor-risk cytogenetics were more common in P-gp(+) patients. P-gp expression and cytogenetics were correlated, though independent prognostic factors. We conclude that zosuquidar did not improve outcome in older acute myeloid leukemia, in part, because of the presence P-gp independent mechanisms of resistance. This trial is registered at www.clinicaltrials.gov as #NCT00046930.
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PMID:Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999. 2108 39

Rhodamine 123 (RH-123) and its glucuronidated metabolite (RH-Glu) are excreted into the bile via the ABC efflux transporters P-glycoprotein (P-gp) and multidrug resistance-related protein type 2 (Mrp2), respectively. In this study, we investigated the short-term (2 h) effects of a low or high concentration of nitric oxide (NO) donors sodium nitroprusside (SNP) and isosorbide dinitrate (ISDN) on the hepatobiliary disposition of RH-123 and its metabolite in an isolated perfused rat liver model. Additionally, the effects of ISDN on the hepatobiliary disposition of 5 (and 6)-carboxy-2', 7'- dichlorofluorescein (CDF), a specific marker of Mrp2, were investigated in the same model. Whereas SNP caused a substantial (85-90%) reduction in the P-gp- and Mrp2-mediated transport of RH-123 and RH-Glu, respectively, ISDN did not affect either of these transporters. However, ISDN reduced the biliary recovery of RH-Glu, most likely because of inhibition of the formation of the metabolite. Further studies showed that the effects of SNP on these transporters are due to a substantial (88%) depletion of hepatic ATP levels by this NO donor. Additionally, studies using CDF revealed an almost identical hepatobiliary disposition of this Mrp2 marker in the presence or absence of ISDN. It is concluded that short-term exposure of rat livers to NO does not affect the functions of the efflux transporters P-gp and Mrp2. The observed inhibitory effects of SNP on the functions of both P-gp and Mrp2 are via an NO-independent mechanism.
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PMID:Divergent effects of nitric oxide donors on the biliary efflux transporters in isolated perfused rat livers: nitric oxide-independent inhibition of ABC transporters by sodium nitroprusside. 2119 35

Breast cancer resistance protein (BCRP/ABCG2) confers resistance to anticancer drugs such as 7-ethyl-10-hydroxycamptothecin (SN-38, an active metabolite of irinotecan), mitoxantrone, and topotecan. In this study, we examined the reversing effects of YHO-13177, a novel acrylonitrile derivative, and its water-soluble diethylaminoacetate prodrug YHO-13351 on the BCRP-mediated drug resistance. YHO-13177 potentiated the cytotoxicity of SN-38, mitoxantrone, and topotecan in both BCRP-transduced human colon cancer HCT116 (HCT116/BCRP) cells and SN-38-resistant human lung cancer A549 (A549/SN4) cells that express BCRP, but had little effect in the parental cells. In addition, YHO-13177 potentiated the cytotoxicity of SN-38 in human lung cancer NCI-H460 and NCI-H23, myeloma RPMI-8226, and pancreatic cancer AsPC-1 cells that intrinsically expressed BCRP. In contrast, it had no effect on P-glycoprotein-mediated paclitaxel resistance in MDR1-transduced human leukemia K562 cells and multidrug resistance-related protein 1-mediated doxorubicin resistance in MRP1-transfected human epidermoid cancer KB-3-1 cells. YHO-13177 increased the intracellular accumulation of Hoechst 33342, a substrate of BCRP, at 30 minutes and partially suppressed the expression of BCRP protein at more than 24 hours after its treatment in both HCT116/BCRP and A549/SN4 cells. In mice, YHO-13351 was rapidly converted into YHO-13177 after its oral or intravenous administration. Coadministration of irinotecan with YHO-13351 significantly increased the survival time of mice inoculated with BCRP-transduced murine leukemia P388 cells and suppressed the tumor growth in an HCT116/BCRP xenograft model, whereas irinotecan alone had little effect in these tumor models. These findings suggest that YHO-13351, a prodrug of YHO-13177, could be clinically useful for reversing BCRP-mediated drug resistance in cancer chemotherapy.
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PMID:Novel acrylonitrile derivatives, YHO-13177 and YHO-13351, reverse BCRP/ABCG2-mediated drug resistance in vitro and in vivo. 2156 63

Studies demonstrated that chronic renal failure (CRF) affects the expression and activity of intestinal, hepatic, and renal drug transporters. Such drug transporters are expressed in brain cells and at the blood-brain barrier (BBB), where they limit the entry and distribution of drugs in the brain. Perturbations in brain drug transporter equilibrium by CRF could lead to central drug toxicity. This study evaluates how CRF affects BBB drug transporters using a 5/6 nephrectomized rat model. Protein and mRNA expression of influx transporters [organic anion-transporting polypeptide (Oatp), organic anion transporter (Oat)] and efflux transporters [P-glycoprotein (P-gp), multidrug resistance-related protein (Mrp), breast cancer resistance protein (Bcrp)] were measured in CRF and control rat brain. Intracerebral accumulation of radiolabeled benzylpenicillin, digoxin, doxorubicin, and verapamil was used to evaluate BBB drug permeability. Protein expression of the transporters was evaluated in rat brain endothelial cells (RBECs) and astrocytes incubated with control and CRF rat serum. We demonstrated significant decreases (30-50%) in protein and mRNA levels of Bcrp, Mrp2 to -4, Oat3, Oatp2 and -3, and P-gp in CRF rat brain biopsies, as well as in astrocytes and RBECs incubated with CRF serum. These decreases did not correlate with in vivo changes because BBB permeability of benzylpenicillin was decreased by 30% in CRF rats, whereas digoxin, doxorubicin, and verapamil permeabilities were unchanged. It thus seems that even with decreased drug transporters, BBB integrity and function is conserved in CRF.
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PMID:Effects of chronic renal failure on brain drug transporters in rats. 2196 19

The multidrug resistance (MDR) phenotype is frequently associated with the overexpression of transmembrane drug proteins such as the P-glycoprotein (Pgp) and/or multidrug resistance related protein-1 (MRP1). These proteins belong to the superfamily of the so-called ATP-binding cassette superfamily and act as drug efflux pumps of a broad range of chemotherapeutic agents commonly used in the treatment of malignancies. These proteins have been found to be overexpressed in both haematological and solid tumours and are considered as adverse prognostic factors. The ability to obtain in vivo and non-invasively information regarding the functional activity of MDR-related transporters, using probes that mimic the antineoplastic agents, provide a very useful tool in the clinical setting by determining the individual tumour susceptibility to chemotherapy. This previous knowledge could serve as a critical tool for optimizing chemotherapeutic protocols on a patient-specific basis. The emergence of non-invasive molecular imaging techniques using radiolabelled probes provides an interesting approach for functional assessment of the classical mechanism of MDR in cancer patients. Toward this objective, the clinically approved 99mTc-labelled cationic lipophilic complexes (sestamibi and tetrofosmin) have been characterized as transport substrates of Pgp and MRP1 and proposed as surrogate markers of chemotherapeutic agents for functional evaluation of MDR by single-photon emission tomography (SPECT). Here we review the potential applications of these agents in identifying drug resistance mechanisms based on functional assays and their potential as a tool for evaluating the efficacy of MDR inhibitors, using cellular and animal models of chemoresistance.
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PMID:Cationic lipophilic radiotracers for functional imaging of multidrug resistance. 2228 Jan 11


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