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

---

Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multidrug resistance (MDR) mediated by overexpression of MDR1 P-glycoprotein (Pgp) is one of the best characterized barriers to chemotherapy in cancer patients. Furthermore, the protective function of Pgp-mediated efflux of xenobiotics in various organs has a profound effect on the bioavailability of drugs in general. Thus, there is an expanding requirement to noninvasively interrogate Pgp transport activity in vivo. We herein report the Pgp recognition properties of a novel 99mTc(I)-tricarbonyl complex, [99mTc(CO)3(MIBI)3]+ (Tc-CO-MIBI). Tc-CO-MIBI showed 60-fold higher accumulation in drug-sensitive KB 3-1 cells compared to colchicine-selected drug-resistant KB 8-5 cells. In KB 8-5 cells, tracer enhancement was observed with the potent MDR modulator LY335979 (EC50 = 62 nM). Similar behavior was observed using drug-sensitive MCF-7 breast adenocarcinoma cells and MCF-7/MDR1 stable transfectants, confirming that Tc-CO-MIBI is specifically excluded by overexpression of MDR1 Pgp. By comparison, net accumulation in control H69 lung tumor cells was 9-fold higher than in MDR-associated protein (MRP1)-expressing H69AR cells, indicating only modest transport by MRP1. Biodistribution analysis following tail vein injection of Tc-CO-MIBI showed delayed liver clearance as well as enhanced brain uptake and retention in mdr1a/1b(-/-) gene deleted mice versus wild-type mice, directly demonstrating that Tc-CO-MIBI is a functional probe of Pgp transport activity in vivo.
...
PMID:Characterization of a novel 99mTc-carbonyl complex as a functional probe of MDR1 P-glycoprotein transport activity. 1292 Aug 58

The aim of the study was to determine the effects on the transport of propranolol across monolayers of the human colon adenocarcinoma cell line, Caco-2, of forming a prodrug by conjugating to generation 3 (G3) and lauroyl-G3 PAMAM dendrimers. Propranolol is a poorly soluble drug and known substrate of the P-glycoprotein (P-gp) efflux transporter. Propranolol-G3 dendrimer conjugates were synthesised by surface attachment of two, four or six propranolol molecules. The apical (A) to basolateral (B) apparent permeability coefficient, P(app), of propranolol was increased and its B-->A P(app) decreased following conjugation to G3 dendrimers. Conjugation of propranolol to lauroyl-G3 dendrimers further increased its A-->B P(app). Our findings show that the A-->B P(app) of propranolol conjugates was reduced in the presence of the endocytosis inhibitor colchicine and was lower at 4 degrees C than at 37 degrees C, suggesting that the enhancement mechanism involves endocytosis-mediated transepithelial transport. The A-->B P(app) of conjugated propranolol was not altered in the presence of the P-gp inhibitor cyclosporin A suggesting that conjugation of drug to dendrimer allows the bypassing of the efflux transporter. The results suggest that dendrimer-drug prodrugs may be used to increase drug solubility and bypass drug efflux transporters, therefore increasing drug bioavailability.
...
PMID:The use of a dendrimer-propranolol prodrug to bypass efflux transporters and enhance oral bioavailability. 1502 56

In vitro studies demonstrated that the accumulation of 2-deoxy-D-glucose was reduced in multidrug resistant cell lines. In animal study, it has been suggested that 2-[18F]fluoro-2-deoxy-D-glucose (FDG) may be a marker for multidrug resistance (MDR). The aim of this clinical study was to compare MDR characteristics by immunohistochemical assay with FDG uptake and investigate whether FDG is a marker for MDR in patients with untreated lung cancer. Forty-seven patients with 49 untreated lung cancers, who had undergone both preoperative FDG PET imaging and thoracotomy, were enrolled in this study. Before surgery, FDG PET was performed 40 min after injection, and standardized uptake values (SUVs) were obtained. Patients were classified into low-SUV (< or = 5) and high-SUV (> 5) groups. After surgery, the expression of P-glycoprotein (Pgp) was investigated by immunohistochemistry, and the lung cancer FDG uptake was analysed for possible association with Pgp expression. The strong intensity of Pgp immunoreactivity was seen only in the low-SUV group. The percentage of the Pgp positive area was significantly lower in the high-SUV group (21.7 +/- 13.4%) than in the low-SUV group (44.1 +/- 29.7%) (P = 0.015). In the high-SUV group, the percentage of Pgp positive area did not exceed 50%. In lung adenocarcinoma, the intensity of Pgp immunoreactivity and the percentage of Pgp positive area increased with degree of cell differentiation, while FDG uptake decreased with degree of cell differentiation. Bronchioloalveolar carcinoma, in particular, showed overexpression of Pgp and modest uptake of FDG. In conclusion, Pgp expression was found to be inversely related to FDG uptake in untreated lung cancer. Pgp expression correlated with the degree of cell differentiation in adenocarcinomas, whilst FDG uptake was inversely related to cell differentiation. FDG may be an in vivo marker for MDR in patients with untreated lung cancer.
...
PMID:P-glycoprotein expression is associated with FDG uptake and cell differentiation in patients with untreated lung cancer. 1506 Dec 61

The objective of this investigation was to evaluate the effects of two dietary isothiocyanates (ITCs), benzyl- (BITC) and phenethyl isothiocyanate (PEITC), and one synthetic ITC, alpha-naphthyl isothiocyanate (1-NITC), on the P-glycoprotein (P-gp)- and multidrug-resistance protein 1 (MRP1)-mediated efflux of daunomycin (DNM), determine whether PEITC is a substrate of P-gp and/or MRP1, and elucidate the mechanism(s) involved in the inhibition of transport. BITC, PEITC, and 1-NITC significantly increased the 2-h accumulation of DNM in MCF-7/ADR (P-gp overexpression), PANC-1 (MRP1 overexpression), and human colon adenocarcinoma Caco-2 cells (except for 1-NITC). The accumulation of (14)C-PEITC was not changed in Caco-2, human breast cancer MDA435/LCC6 and MDA435/LCC6MDR1 (P-gp overexpression) cells in the absence and presence of the P-gp inhibitor verapamil, but significantly increased with the MRP inhibitor MK571 in PANC-1 cells. The isocyanate and amine metabolites had no effect on DNM accumulation in any cell line. After 2- and 24-h ITC treatments, cellular concentrations of glutathione (GSH) in PANC-1 and Caco-2 cells were depleted by BITC and PEITC, but not by 1-NITC; glutathione-S-transferase activity exhibited small changes. Our results suggest that (1) BITC, PEITC, and 1-NITC inhibit the P-gp- and MRP1-mediated efflux of DNM; (2) PEITC and/or its conjugates do not represent P-gp substrates; (3) BITC and PEITC, but not 1-NITC, inhibit MRP1 through the depletion of intracellular GSH, which acts as a cosubstrate for DNM efflux via MRP1; and (4) PEITC and/or its conjugates are MRP1 substrates so binding interactions with DNM represent a second potential mechanism involved in MRP1 inhibition.
...
PMID:Effects of benzyl-, phenethyl-, and alpha-naphthyl isothiocyanates on P-glycoprotein- and MRP1-mediated transport. 1517 77

Multidrug resistance (MDR) has been studied extensively because it is one of major problems in cancer chemotherapy. The MDR phenotype is often due to overexpression of P-glycoprotein (P-gp), that acting as an energy-dependent drug efflux pump exports various anticancer drugs out of cells. The major goal of our investigation is to establish whether bovine serum amine oxidase (BSAO), which generates the products H(2)O(2) and aldehyde(s), from the polyamine spermine, is able to overcome MDR of human cancer cells. The cytotoxicity of the products was evaluated in both drug-sensitive (LoVo WT) and drug-resistant (LoVo DX) colon adenocarcinoma cells. A clonogenic cell survival assay demonstrated that LoVo DX cells were more sensitive than LoVo WT cells. Exogenous catalase protected cells against cytotoxicity mainly due to the formation of H(2)O(2). However, spermine-derived aldehyde(s) still induced some cytotoxicity. The cytotoxic effect was totally inhibited in the presence of both enzymes, catalase and NAD-dependent aldehyde dehydrogenase (ALDH). Transmission electron microscopy investigations showed that BSAO and spermine induced evident mitochondria alterations, more pronounced in MDR than in LoVo WT cells. The mitochondrial activity was checked by flow cytometry studies, labelling cells with the probe JC1, that displayed a basal hyperpolarized status of the mitochondria in multidrug-resistant cells. After treatment with amine oxidase in the presence of polyamine-spermine, the cells showed a marked increase in mitochondrial membrane depolarization higher in LoVo DX than in LoVo WT cells. Our findings suggest that toxic oxidation products formed from spermine and BSAO could be a powerful tool in the development of new anticancer treatments, mainly against MDR tumor cells.
...
PMID:Mitochondrial alterations induced by serum amine oxidase and spermine on human multidrug resistant tumor cells. 1522 8

Caveolin-1, the principal component of caveolae, is a 21-24 kDa integral membrane protein. The interaction of the caveolin-1 scaffolding domain with signaling molecules can functionally inhibit the activity of these signaling proteins. Little is known about how caveolin-1 influences the expression of P-glycoprotein (P-gp), an ABC transporter encoded by multi-drug resistance (MDR1) gene. To elucidate the possible mechanism between caveolin-1 and P-gp expression, in the present study, we overexpressed caveolin-1 in the Hs578T/Dox breast adenocarcinoma cells, a multidrug resistant line, and then selected single clone cells highly expressing caveolin-1 level. Both Western blot and confocal microscopy analyses showed that caveolin-1 was markedly overexpressed in the transfectants, while P-gp protein was almost abolished. Reverse transcription polymerase chain reaction also showed that the expression of P-gp mRNA was significantly suppressed in the transfectants. It was confirmed further by Northern blot analysis. Moreover, through measuring the changes of drug resistance and P-gp transport activity in the transfectants, we found that overexpression of caveolin-1 reversed drug resistance of transfectants and lowered their P-gp transport activity to the level of Hs578T/S. Taken together, our results indicate that such suppression of P-gp in the transfectants overexpressing caveolin-1 may occur at the transcriptional level.
...
PMID:Suppression of P-glycoprotein gene expression in Hs578T/Dox by the overexpression of caveolin-1. 1549 65

Efflux of cytotoxic agents mediated by P-glycoprotein is believed to be an important mechanism of multidrug resistance, which remains a serious limitation to successful chemotherapy in cancers such as metastatic breast cancer. A series of 4-aryl-1,4-dihydropyridines and corresponding aromatized 4-arylpyridines have been synthesized based on structure modifications of niguldipine to enhance multidrug resistance reversal activity, while minimizing calcium channel binding. Thirty new compounds were characterized. [(3)H]Vinblastine accumulation studies indicated that at a concentration level of 3 muM, 15 of 18 4-aryl-1,4-dihydropyridines and all 4-arylpyridines can successfully restore intracellular accumulation of vinblastine in a resistant human breast adenocarcinoma cell line, MCF-7/adr, which overexpresses P-glycoprotein. The most potent compounds led to an approximately 15-fold increase of vinblastine accumulation. All of the test compounds that significantly increased vinblastine accumulation in MCF/adr cells were able to substantially reduce IC(50) values of daunomycin and increase its cytotoxicity in MCF-7/adr-resistant cells, confirming the results of the vinblastine accumulation studies. Calcium channel binding assays for these newly synthesized compounds were conducted using rat cerebral cortex membrane. All but eight compounds demonstrated negligible calcium channel binding over the concentration range from 15 to 2500 nM. The results demonstrate that the newly synthesized series of 1,4-dihydropyridines and pyridines represent P-glycoprotein modulators with negligible calcium channel blocking activity.
...
PMID:New 4-aryl-1,4-dihydropyridines and 4-arylpyridines as P-glycoprotein inhibitors. 1558 8

Pancreatic ductal adenocarcinoma is among the top 10 causes of death from cancer in industrialized countries. In comparison with other gastrointestinal malignancies, pancreatic cancer is one of the tumors most resistant to chemotherapy. An important mechanism of tumor multidrug resistance is increased drug efflux mediated by several transporters of the ABC superfamily. Especially BCRP (ABCG2), MDR1 P-glycoprotein (ABCB1) and members of the MRP (ABCC) family are important in mediating drug resistance. The MRP family consists of 9 members (MRP1-MRP9) with MRP1-MRP6 being best characterized with respect to protein localization and substrate selectivity. Here, we quantified the mRNA expression of BCRP and of all MRP family members in normal human pancreas and pancreatic carcinoma and analyzed the mRNA level of the transporters most abundantly expressed in pancreatic tissue, BCRP, MRP1, MRP3, MRP4 and MRP5, in 37 tissue samples. In addition, we determined the localization of the 4 MRP proteins in normal human pancreas and in pancreatic carcinoma. The expression of BCRP, MRP1 and MRP4 mRNA did not correlate with tumor stage or grading. On the other hand, the expression of MRP3 mRNA was upregulated in pancreatic carcinoma samples and was correlated with tumor grading. The MRP5 mRNA level was significantly higher in pancreatic carcinoma tissue compared to normal pancreatic tissue. These data suggest that MRP3 and MRP5 are involved in drug resistance of pancreatic tumors and that quantitative analysis of their expression may contribute to predict the benefit of chemotherapy in patients with pancreatic cancer.
...
PMID:Expression and localization of human multidrug resistance protein (ABCC) family members in pancreatic carcinoma. 1568 70

Interference with microtubule function is a promising antitumoral concept. Paclitaxel is a clinically validated tubulin-targeting agent; however, treatment with paclitaxel is often limited by taxane-related toxicities and is ineffective in tumors with multidrug-resistant cells. Patupilone (EPO906, epothilone B) is a novel non-taxane-related microtubule-stabilizing natural compound that retains full activity in multidrug-resistant tumors and is clinically less toxic than paclitaxel. Here we have investigated the effect of combined treatment with ionizing radiation and patupilone or paclitaxel in the P-glycoprotein-overexpressing, p53-mutated human colon adenocarcinoma cell line SW480 and in murine, genetically defined E1A/ras-transformed paclitaxel-sensitive embryo fibroblasts. Patupilone and paclitaxel alone and in combination with ionizing radiation reduced the proliferative activity of the E1A/ras-transformed cell line with similar potency in the sub and low nanomolar range. SW480 cells were only sensitive to patupilone, and combined treatment with low-dose patupilone (0.1 nmol/L) followed by clinically relevant doses of ionizing radiation (2 and 5 Gy) resulted in a supra-additive cytotoxic effect. Inhibition of the drug efflux protein P-glycoprotein with verapamil resensitized SW480 cells to treatment with low doses of paclitaxel alone and in combination with IR. In tumor xenografts derived from SW480 cells a minimal treatment regimen with patupilone and fractionated irradiation (1 x 2 mg/kg plus 4 x 3 Gy) resulted in an at least additive tumor response with extended tumor growth arrest. Analysis by flow cytometry in vitro revealed an apoptosis- and G(2)-M-independent mode of radiosensitization by patupilone. Interestingly though, a transient accumulation of cells in S phase was observed on combined treatment.Overall, patupilone might be a promising alternative in paclitaxel-resistant, P-glycoprotein-overexpressing tumors for a combined treatment regimen using ionizing radiation and a microtubule inhibitor.
...
PMID:Patupilone acts as radiosensitizing agent in multidrug-resistant cancer cells in vitro and in vivo. 1574 64

A study was performed to improve cytotoxicity determinations by eliminating flavin-mediated photosensitization from tests with KB cells, NCI-H69 cells, P-glycoprotein expressing KBC5-8 cells, MRP1-expressing H69AR cells, and A240286S human lung adenocarcinoma cells. Growth inhibition by cis-platin, doxorubicin, etoposide, gemcitabine, taxol, vincristine, vinblastine, and vinorelbine was determined under flavin-protecting conditions using flavin-free culture media with fetal bovine serum as the only source of flavins. As compared to conventional tests, the IC50 values determined under flavin-protecting conditions reflected increased apparent drug cytotoxicities, and were flawlessly reproducible. Flavin-mediated photosensitization should, therefore, be strictly eliminated from in vitro experiments involving cytotoxic and other drugs.
...
PMID:Cytotoxicity determination without photochemical artifacts. 1589 Feb 37


<< Previous 1 2 3 4 5 6 7 8 9 10

---