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)

Mixed micelles prepared of poly(ethylene glycol)2000-phosphatidyl ethanolamine conjugate (PEG(2000)-PE) and d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) in 1:1 molar ratio have been investigated. Micelle formation was confirmed by NMR spectroscopy. CMC of the micelles was found to be 1.5 x 10(-5)M. Poorly soluble anti-cancer drug paclitaxel (PCL) was efficiently solubilized in 15 nm non-toxic PEG-PE/TPGS micelles. PCL entrapment was quite stable with only about 20% of the incorporated drug released from micelles after 48 h at 37 degrees C. In addition, PCL-containing PEG(2000)-PE/TPGS micelles were stable in vitro under various conditions modeling the physiological ones, in particular, at low pH values and in the presence of bile acids, which is especially important for their possible oral administration. Fluorescently labeled micelles demonstrated time-dependent internalization by human colon adenocarcinoma cell line, Caco-2. The internalization of PEG(2000)-PE/TPGS micelles loaded with P-glycoprotein (P-gp) substrate, rhodamine-123 (RH-123), opposite to the internalization of the free RH-123, was not influenced by the inhibition of the P-gp pump with verapamil hydrochloride, which assumes a P-gp-independent micelle internalization.
...
PMID:Polyethylene glycol-phosphatidylethanolamine conjugate (PEG-PE)-based mixed micelles: some properties, loading with paclitaxel, and modulation of P-glycoprotein-mediated efflux. 1661 18

Active extrusion of drugs from the cell interior by primary and secondary efflux pumps is an essential mechanism underlying the phenomenon of multidrug resistance. The first discovered and best characterized primary efflux pump found in humans is the ABC transporter P-glycoprotein (PGP), which shows very broad substrate specificity. Many of these molecules are lipophilic, and binding most likely takes place within the membrane. PGP could either translocate them from the inner to the outer leaflet (flippase) or extrude them from the membrane into the extracellular environment (hydrophobic vacuum cleaner). Recognition and binding of such a diverse set of substrates must be associated with a preferred membrane location, determined by molecular properties and lipid interactions. Therefore, a systematic study of the interaction among seven PGP substrates (phenazine, doxorubicin, cephalexin, ampicillin, chloramphenicol, penicillin G, and quercetin) and two modulators (quinidine and nicardipine) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) model membranes is reported here. The location profile of these molecules across the membrane was determined by (1)H NOESY MAS NMR based on (1)H-(1)H cross-peaks between their aromatic fingerprint region and lipid resonances. Although structurally rather diverse, all tested substances are found to have their highest concentration between the phosphate of the lipid headgroup and the upper segments of the lipid hydrocarbon chains. Our findings are consistent with PGP substrate and modulator binding from the membrane interface region.
...
PMID:Localization of multidrug transporter substrates within model membranes. 1668 93

Recent advances in the design and preclinical evaluations of promising new generation taxane anticancer agents are reviewed in this article. Paclitaxel and docetaxel are two of the most important anticancer drugs today. However, recent reports have shown that treatment with these drugs often encounters undesirable side effects as well as drug resistance. Therefore, it is important to develop new taxane anticancer agents with fewer side effects, superior pharmacological properties, and improved activity against drug-resistant human cancers. Structure-activity relationship (SAR) studies led to the discovery of a series of highly active second-generation taxanes. One of them, "Ortataxel" (SB-T-101131, IDN5109, BAY59-8862), exhibits excellent activity against a variety of drug-sensitive and drug-resistant cancer cell lines, as well as human tumor xenografts in mice. It is orally active and is currently in phase II clinical trials. Photoaffinity labeling of microtubules and P-glycoprotein using photoreactive radiolabeled taxoids has disclosed the drug-binding domain of tubulin as well as Pgp. Together with information on microtubule-bound fluorine-labeled taxoids obtained by solid-state NMR studies, the bioactive conformation of paclitaxel and taxoids appears to emerge. Novel taxane-monoclonal antibody (mAb) immunoconjugates, have shown highly promising results for the tumor-specific delivery and release of an extremely cytotoxic, second-generation taxane. Also, another novel series of second generation taxanes conjugated with n-3 polyunsaturated fatty acids, e.g. decosahexaenoic acid (DHA), has exhibited impressive antitumor activity with minimum general toxicity against the highly drug-resistant DLD-1 human colon cancer xenografts in SCID mice.
...
PMID:Recent advances in the new generation taxane anticancer agents. 1678 8

Verapamil and amlodipine are calcium ion influx inhibitors of wide clinical use. They are partially charged at neutral pH and exhibit amphiphilic properties. The noncharged species can easily cross the lipid membrane. We have measured with solid-state NMR the structural changes induced by verapamil upon incorporation into phospholipid bilayers and have compared them with earlier data on amlodipine and nimodipine. Verapamil and amlodipine produce a rotation of the phosphocholine headgroup away from the membrane surface and a disordering of the fatty acid chains. We have determined the thermodynamics of verapamil partitioning into neutral and negatively charged membranes with isothermal titration calorimetry. Verapamil undergoes a pK-shift of DeltapK(a) = 1.2 units in neutral lipid membranes and the percentage of the noncharged species increases from 5% to 45%. Verapamil partitioning is increased for negatively charged membranes and the binding isotherms are strongly affected by the salt concentration. The electrostatic screening can be explained with the Gouy-Chapman theory. Using a functional phosphate assay we have measured the affinity of verapamil, amlodipine, and nimodipine for P-glycoprotein, and have calculated the free energy of drug binding from the aqueous phase to the active center of P-glycoprotein in the lipid phase. By combining the latter results with the lipid partitioning data it was possible, for the first time, to determine the true affinity of the three drugs for the P-glycoprotein active center if the reaction takes place exclusively in the lipid matrix.
...
PMID:Interaction of verapamil with lipid membranes and P-glycoprotein: connecting thermodynamics and membrane structure with functional activity. 1687 10

The hydroxystilbene trans-3,5,3',4'-tetrahydroxystilbene (piceatannol) (1), isolated from the methanol extract of Euphorbia lagascae defatted seeds, was methylated to yield the derivatives trans-3,5,3',4'-tetramethoxystilbene (2), (trans-3,5-dihydroxy-3',4'-dimethoxystilbene) (3) and trans-3,5,3'-trihydroxy-4'-methoxystilbene (4). The structures of the compounds were assigned by spectroscopic methods (IR, 1H-NMR, 13C-NMR and MS). The ability of piceatannol (1) and the three methylated derivatives to modulate the transport activity of P-glycoprotein (P-gp) and apoptosis induction on the L5178 mouse lymphoma cell line containing the human MDR1 gene was studied by flow cytometry. The reversal of multidrug-resistance (MDR) was investigated by measuring the accumulation of rhodamine-123, a fluorescent substrate analog of doxorubicin, in cancer cells. Verapamil was applied as a positive control. For the evaluation of the compounds as apoptosis inducers, tumor cells were stained with FITC-labelled annexin-V and propidium iodide. The tetramethylated derivative (2) was found to be a powerful inhibitor of P-gp activity. Compounds 1 and 2 showed an increased apoptotic effect in the MDR subline, the most active being piceatannol (1). Furthermore, in the combination chemotherapy model, the interaction between doxorubicin and the resistance modifier 2 was studied in vitro. The results of checkerboard experiments indicated that the type of interaction was additive between doxorubicin and compound 2 on the human MDR1 gene-transfected mouse lymphoma cells. However, in the MCF7/dox human breast cancer cells, the interaction was non-additive. The degree of additive and non-additive interactions were close to the borderline of the FIX values corresponding to the two types of interactions.
...
PMID:Interaction between doxorubicin and the resistance modifier stilbene on multidrug resistant mouse lymphoma and human breast cancer cells. 1709 79

CeNA is an oligonucleotide where the (deoxy)ribose sugars have been replaced by cyclohexenyl moieties. We have determined the NMR structure of a CeNA:RNA duplex and have modeled this duplex in the crystal structure of a PIWI protein. An N puckering of the ribose nucleosides, a 2H3 conformation of the cyclohexenyl nucleosides, and an A-like helix conformation of the backbone, which deviates from the standard A-type helix by a larger twist and a smaller slide, are observed. The model of the CeNA:RNA duplex bound to the PIWI protein does not show major differences in the interaction of the guide CeNA with the protein when compared with dsRNA, suggesting that CeNA modified oligonucleotides might be useful as siRNAs. Incorporation of one or two CeNA units in the sense or antisense strands of dsRNA led to similar or enhanced activity compared to unmodified siRNAs. This was tested by targeting inhibition of expression of the MDR1 gene with accompanying changes in P-glycoprotein expression, drug transport, and drug resistance.
...
PMID:Structural characterization and biological evaluation of small interfering RNAs containing cyclohexenyl nucleosides. 1761 27

A new series of diterpenes, the jatrophanes euphoscopin M (1), euphoscopin N (2) and euphornin L (3), and the lathyrane euphohelioscopin C (7) were isolated from plants of Euphorbia helioscopia L., together with four other known analogues, euphoscopin C (4), euphornin (5), epieuphoscopin B (6) and euphohelioscopin A (8). The new compound stereostructures were elucidated by NMR analysis and computational data. The resulting isolated diterpenes were found to be potent inhibitors of P-glycoprotein (ABCB1), while showing an absence of significant activity against BCRP (ABCG2), despite the high substrate overlapping of these transporters, thus including them in the third-generation class of specific multidrug transporter modulators.
...
PMID:Discovery of a new series of jatrophane and lathyrane diterpenes as potent and specific P-glycoprotein modulators. 1845 10

The microtubule binding affinities of a series of synthetic taxanes have been measured with the aims of dissecting individual group contributions and obtaining a rationale for the design of novel compounds with the ability to overcome drug resistance. As previously observed for epothilones, the positive and negative contributions of the different substituents to the binding free energies are cumulative. By combining the most favorable substitutions we increased the binding affinity of paclitaxel 500-fold. Insight into the structural basis for this improvement was gained with molecular modeling and NMR data obtained for microtubule-bound docetaxel. Taxanes with affinities for microtubules well above their affinities for P-glycoprotein are shown not to be affected by multidrug resistance. This finding strongly indicates that optimization of the ligand-target interaction is a good strategy to overcome multidrug resistance mediated by efflux pumps.
...
PMID:Optimization of taxane binding to microtubules: binding affinity dissection and incremental construction of a high-affinity analog of paclitaxel. 1855 68

We examined how melatonin absorption was affected by pharmaceutical excipients using the Ussing chamber technique with mounted rat gastrointestinal (GI) segments. Melatonin absorption occurs throughout the GI tract, with the greatest absorption being in the rectum and ileum and the least in the stomach. Melatonin can be classified as a low permeability drug. P-glycoprotein (P-gp) does not affect melatonin absorption but transported rhodamine 123, a well-known P-gp substrate. The possibility of saturating P-gp by melatonin was excluded. Sodium cholate (0.5%) increased melatonin absorption, but decreased absorption at higher concentrations (1.0% and 5.0%). Sodium oleate (0.5% and 1.0%) consistently decreased melatonin absorption. Pharmaceutical excipients increased the absorption of Lucifer yellow (100 microg/mL), a paracellular probe but decreased the absorption of melatonin above the critical micelle concentration (cmc), suggesting that melatonin was transported mainly by transcellular pathway. Sodium cholate and sodium oleate, when above the cmc, resulted in micellar complexes as revealed by (1)H NMR spectra and particle size distribution. Histology tests showed mucosal damage of jejunum tissues in the presence of these excipients. The balance of tissue damage by the formation of micellar complexes could affect the melatonin absorption. This information on melatonin absorption behaviors and its modulation by pharmaceutical excipients can be used in further oral dosage formulations to affect circadian rhythm.
...
PMID:New findings on melatonin absorption and alterations by pharmaceutical excipients using the Ussing chamber technique with mounted rat gastrointestinal segments. 1946 96

A bioassay-guided separation protocol, including the testing of the extracts, fractions and pure compounds for their ability to inhibit P-glycoprotein (the efflux pump responsible for the multidrug resistance of the used cell line) of mouse lymphoma cells containing the human efflux pump gene MDR1, led to the isolation of seven compounds from the chloroform and ethyl acetate soluble fractions of the methanolic extract of Carpobrotus edulis. The compounds were identified by 1D, 2D NMR and MS investigations as triterpens (beta-amyrin, uvaol and oleanolic acid), monogalactosyldiacylglycerol, catechin, epicatechin and procyanidin B5. Uvaol was the most effective and promising compound in the reversal of multidrug resistance in MDR mouse lymphoma cell line.
...
PMID:Constituents of Carpobrotus edulis inhibit P-glycoprotein of MDR1-transfected mouse lymphoma cells. 2039 3


<< Previous 1 2 3 4 5 6 7 8 9 Next >>

---