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)

Phospholipid bilayers, 40 A thick, were generated as electron microscope substrates by submerging copper grids overlaid with holey plastic through a lipid monolayer on a water surface. Previously formed proteoliposomes containing single-particle membrane proteins in their bilayers were then fused into the newly formed bilayer substrate. To demonstrate this methodology, multi-drug resistance protein P-glycoprotein was incorporated into these bilayers and imaged by fixed beam microscopy and scanning transmission electron microscopy.
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PMID:Freestanding lipid bilayers as substrates for electron cryomicroscopy of integral membrane proteins. 1187 25

Studies of the multidrug-resistance protein 1 (MRP1) have been hampered by the lack of a simple expression system allowing for rapid generation of mutants and yielding milligram amounts of protein. Here, we describe a Saccharomyces cerevisiae expression system that meets those conditions. MRP1 was expressed under the control of the constitutive PMA1 (yeast proton pump) promoter. The best conditions for expression were determined, including the use of the chemical chaperone glycerol, which increased MRP1 expression. N-terminal poly-histidine or FLAG affinity tags reduce MRP1 expression, whereas the same tags fused to the C-terminus had no effect. All the fusion proteins were functional. We conclude that because of its low cost and simplicity, the S. cerevisiae-based MRP1-expression system will be useful for studies where a large number of mutants or milligram amounts of purified MRP1 are needed.
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PMID:Expression of functional multidrug-resistance protein 1 in Saccharomyces cerevisiae: effects of N- and C-terminal affinity tags. 1281 67

The transport of drugs into the brain is prevented in most cases by the presence of the blood brain barrier (BBB). Endothelial cells in the brain of vertebrates are fused together by tight junctions that eliminate the normal pathways of free diffusion existing in the capillary beds of organs other than the brain or spinal cord. Therefore, a molecule that has a molecular weight less than a 500 Dalton can cross the BBB in proportion to lipid solubility. Recent molecular biological studies have contributed to the isolation and functional analysis of transporter proteins at the BBB. There are three types of endogenous transport systems: carrier-mediated transporters, active efflux transporters such as P-glycoprotein, and receptor-mediated transcytosis systems. The structural and functional integrity of the BBB has appeared to be dramatically altered by various diseases of the CNS such as ischemia, anoxia and inflammation, resulting in cerebral edema and damage to the neurons. General anesthetic agents can alter the BBB function. For example, the degree of the BBB disruption was smaller during isoflurane anesthesia than during pentobarbital anesthesia. In this review, we focus on recent progress in the BBB research and functional modulation produced by general anesthetics.
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PMID:[Blood-brain barrier and general anesthetics]. 1367 73

Sphingolipid-metabolizing enzymes control the dynamic balance of the cellular levels of bioactive lipids, including the proapoptotic compound ceramide and the proliferative compound sphingosine 1-phosphate. Accumulating evidence indicates that sphingosine kinase (SK) plays a pivotal role in regulating tumor growth and that SK can act as an oncogene. Despite the importance of SK for cell proliferation, pharmacological inhibition of SK is an untested means of treating cancer because of the current lack of nonlipid inhibitors of this enzyme. To further assess the involvement of SK in human tumors, levels of RNA for SK in paired samples of cDNA prepared from tumors and normal adjacent tissue were analyzed. Expression of SK RNA was significantly elevated in a variety of solid tumors, compared with normal tissue from the same patient. To identify and evaluate inhibitors of SK, a medium throughput assay for recombinant human SK fused to glutathione S-transferase was developed, validated, and used to screen a library of synthetic compounds. A number of novel inhibitors of human SK were identified, and several representative compounds were characterized in detail. These compounds demonstrated activity at sub- to micromolar concentrations, making them more potent than any other reported SK inhibitor, and were selective toward SK compared with a panel of human lipid and protein kinases. Kinetic studies revealed that the compounds were not competitive inhibitors of the ATP-binding site of SK. The SK inhibitors were antiproliferative toward a panel of tumor cell lines, including lines with the multidrug resistance phenotype because of overexpression of either P-glycoprotein or multidrug resistance phenotype 1, and were shown to inhibit endogenous human SK activity in intact cells. Furthermore, each inhibitor induced apoptosis concomitant with tumor cell cytotoxicity. Methods for the synthesis of a series of aurone inhibitors of SK were established, and a prototypical dihydroxyaurone was found to have moderate antitumor activity in vivo in the absence of overt toxicity to the mice. These compounds are the first examples of nonlipid inhibitors of SK with in vivo antitumor activity and so provide leads for additional development of inhibitors of this important molecular target.
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PMID:Discovery and evaluation of inhibitors of human sphingosine kinase. 1452 23

New antiproliferative compounds, the 1-aryl-3-ethoxycarbonyl-pyrido[2,3-g]isoquinolin-5,10-diones (PIQDs, 1-7), were designed on the basis of a molecular model obtained by aligning the common quinolinquinone substructure of 5H-pyrido[3,2-a]phenoxazin-5-one (PPH) and some known anticancer agents. A Diels-Alder reaction between quinolin-5,8-dione (QD) and a 2-azadiene, formed by demolition of 2-aryl-1,3-thiazolidine ethyl esters (T compounds), was used to produce 1-7 and the isomeric 1-aryl-3-ethoxycarbonylpyrido[3,2-g]isoquinolin-5,10-diones (8-14). Two other compounds, the 3-amino-3-ethoxycarbonyldihydrothieno[2,3-g]quinolin-4,9-dione (15) and the 3-amino-3-ethoxycarbonyldihydrothieno[3,2-g]quinolin-4,9-dione (16), arising from a 1,4 Michael reaction of QD with a thiolate species formed by opening of T compounds, were recovered from the reaction mixture. The antiproliferative activity of 1-16 was evaluated against representative human liquid and solid neoplastic cell lines. The IC(50) of these compounds had median values in the range 2.00-0.01 microM, with 2-4 and 15 exhibiting significantly higher in vitro cytotoxic activity. Compound 2, also evaluated against KB subclones (KB(MDR), KB(7D), and KB(V20C)), was shown to be scarcely subject to the MDR1/P-glycoprotein drug efflux pump responsible for drug resistance. The noncovalent DNA-binding properties of PIQDs were examined using UV-vis and (1)H NMR spectroscopy experiments. Accordingly, these compounds were confirmed to have an ability to intercalate into double-stranded DNA by topoisomerase I superhelix unwinding assay. Interesting structure-activity relationships were found. Three important features seem to contribute to the cytotoxic activity of these anticancer ligands: (i) the DNA intercalating capability of the three-cyclic quinonic system, typical of this class of compounds, (ii) the position of the pendant phenyl ring that, according to the superimposition model, must occupy the same area of the corresponding benzo-fused ring A of PPH, and (iii) the effect of electron-withdrawing substituents on the phenyl ring, which can contribute improving the pi-pi stacking interactions between ligand and DNA base pairs. Besides, a mechanism of action suspected to involve topoisomerases could be hypothesized to interpret the antiproliferative activity of the thienoquinolindione 15, which can be regarded as a cyclic cysteine derivative.
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PMID:Antitumor agents. 3. Design, synthesis, and biological evaluation of new pyridoisoquinolindione and dihydrothienoquinolindione derivatives with potent cytotoxic activity. 1476 Nov 87

The appearance of multidrug resistance (MDR) of tumour cells to a wide array of antitumour drugs, structurally diverse and having different mechanisms of action, constitutes the major obstacle to the successful treatment of cancer. Our approach to search for non-cross resistant antitumour agents is based on the rational design of derivatives, which have a high kinetics of passive cellular uptake rendering their active efflux by MDR exporting pumps inefficient. Recently, two families of acridine cytotoxic agents were obtained, pyrazoloacridines (PACs) and pyrazolopyrimidoacridines (PPACs). The aim of this study was to examine molecular basis of the reported differences in retaining cytotoxic activity of these derivatives at cellular level against resistant erythroleukaemia K562/DOX (overexpressing P-glycoprotein) cell line. The study was performed using a spectrofluorometric method, which allows continuous monitoring of the uptake and efflux of fluorescent molecules by living cells. It was demonstrated that the presence of two additional rings, pyrazole and pyrimidine, fused to the acridine chromophore structure (PPAC) favoured more rapid cellular diffusion than the presence of only one additional pyrazole ring (PAC). The presence of hydrophobic substituent OCH3 markedly favoured the cellular uptake of pyrazoloacridines and pyrazolopyrimidoacridines while compounds having hydrophilic substituent OH exhibited very low kinetics of cellular uptake. In contrast, it was found that neither structure of the ring system nor the hydrophobic/hydrophilic character of examined substituents determined the rate of active efflux of these compounds by P-glycoprotein. Our data showed that a nearly linear relation exists between the resistance factor (RF) and lnV+ reflecting the impact of the cellular uptake rate (V+) on the ability of these compounds to overcome MDR.
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PMID:The role of structural factors in the kinetics of cellular uptake of pyrazoloacridines and pyrazolopyrimidoacridines: implications for overcoming multidrug resistance towards leukaemia K562/DOX cells. 1545 Sep 47

The protein kinase C (PKC) family consists of serine/threonine protein kinases that play important roles in signal transduction, cell proliferation, and tumor formation. Recent studies found that PKCs are commonly overexpressed in human tumors, including soft tissue sarcoma (STS). Overexpression of PKCs contributes to invasion and migration of tumor cells and induction of angiogenesis. PKC can also phosphorylate the multidrug resistance (MDR) gene-encoded P-glycoprotein and induce MDR phenotype. Our previous studies showed that mutation of p53 enhanced STS metastasis and mediated the MDR phenotype. Restoring wild type (WT) p53 in STS cells containing mutant p53 sensitized the cells to chemotherapy. In the present study, we found that PKCalpha protein expression is inhibited by WT p53 partly due to reduced PKCalpha mRNA expression in STS cells, but p53 does not affect PKCalpha mRNA stability. Deletion and mutation analysis of the PKCalpha promoter fused to the luciferase reporter gene identified a Sp1 binding site (-244/-234) in the PKCalpha promoter that is required for p53-mediated inhibition of PKCalpha promoter activity. More importantly, PKCalpha phosphorylates and activates MDR1 P-glycoprotein, whereas inhibition of PKCalpha by p53 leads to decreased MDR1 phosphorylation in STS cells, which sensitizes STS cells to chemotherapeutic agents. These data indicate that WT p53 may resensitize STS to chemotherapeutic agents by reducing MDR1 phosphorylation via transcriptional repression of PKCalpha expression. Thus, molecular-based therapies targeting mutant p53 and PKCalpha may be an effective new strategy to improve chemotherapeutic efficacy in STS.
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PMID:Transcriptional repression of protein kinase Calpha via Sp1 by wild type p53 is involved in inhibition of multidrug resistance 1 P-glycoprotein phosphorylation. 1556 62

Xanthones have been isolated from several natural sources, mainly belonging in Guttiferae and Gentianaceae families as secondary plant metabolites and many of them are endowed with diverse pharmacological properties. We have focused in the study of cytotoxic fused xanthone derivatives, having in mind that some furano- and pyranoxanthone natural products are particularly interesting, in terms of cytotoxic potency and novelty in their mechanism of action and could serve as lead compounds for the development of clinically effective anticancer agents. In this review, a general classification has been attempted based on the type of ring fusion, in such a way that natural compounds as well as synthetic derivatives are discussed. The furanoxanthone psorospermin is a highly promising isolated xanthone derivative exhibiting significant cytotoxicity through a novel mechanism of action, being an irreversible topoisomerase II poison and it was selected for further development as an antineoplastic agent. An important number of pyranoxanthones have been synthesized using as lead compound the acridone alkaloid acronycine. Adducts on the double bond of these compounds provided cytotoxic derivatives possessing cell-cycle selectivity. The synthesis of pyranoxanthones bearing aminosubstituted side-chains resulted in compounds that exhibit markedly improved cytotoxicity towards leukemic and solid tumor cell lines. Azabioisosters of the aminoderivatives exhibit solid tumor selectivity whereas additional pyrazole or/and benzene ring fusion has been incorporated into the xanthone skeleton and resulted in compounds with promising activity, which retain full antiproliferative activity against P-glycoprotein-overexpressing cells. Gambogic acid, a highly effective anticancer drug candidate with low toxicity to normal tissue, together with structurally related representative analogues are also mentioned.
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PMID:Fused xanthone derivatives as antiproliferative agents. 1914 84

We developed the synthesis of a series of thiophene-fused tetracyclic analogues of the antitumor drug ametantrone. The reactions included nucleophilic substitution of methoxy groups in 4,11-dimethoxyanthra[2,3-b]thiophene-5,10-diones with ethylenediamines, producing the derivatives of 4,11-diaminoanthra[2,3-b]thiophene-5,10-dione in good yields. Several compounds showed marked antiproliferative potency against doxorubicin-selected, P-glycoprotein-expressing tumor cells and p53(-/-) cells. The cytotoxicity of some novel compounds for P-glycoprotein-positive cells is highly dependent on N-substituent at the terminal amino group of ethylenediamine moiety. The cytotoxic potency of selected compounds correlated with their ability to attenuate the functions of topoisomerase I and telomerase, strongly suggesting that these enzymes are the major targets of antitumor activity of anthra[2,3-b]thiophene-5,10-dione derivatives.
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PMID:Synthesis and cytotoxic properties of 4,11-bis[(aminoethyl)amino]anthra[2,3-b]thiophene-5,10-diones, novel analogues of antitumor anthracene-9,10-diones. 1920 82

Four series of aromatic carboxylic acids were prepared with a urea or thiourea moiety at the neighboring position to the carboxyl group and benzene or thiophene as aromatic scaffold. Using a calcein AM assay, these compounds were evaluated as inhibitors of multidrug resistance-associated protein 1 (MRP1) and selected compounds were examined toward P-glycoprotein (P-gp) as well as breast cancer resistance protein (BCRP) to assess selectivity for MRP1. Two 2-thioureidobenzo[b]thiophene-3-carboxylic acids (48, 49) were identified as particularly potent inhibitors of MRP1, with IC50 values of around 1 microM. The structural features of this new family of nontoxic MRP1 inhibitors include a (thio)urea disubstituted with preferentially two alkyl groups at the terminal nitrogen and an additional fused aromatic ring.
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PMID:Aromatic 2-(thio)ureidocarboxylic acids as a new family of modulators of multidrug resistance-associated protein 1: synthesis, biological evaluation, and structure-activity relationships. 1958 Mar 19


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