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)

On the basis of physiological localization, broad substrate specificity and energy dependence, the role of the kidney P-glycoprotein was tested in the energy-dependent renal secretion of organic cations. P-glycoprotein-enriched vesicles from Cl 1D/VCR [a multidrug-resistant (MDR) cell line] displayed enhanced transport of the MDR drug vinblastine and the organic cation cimetidine but not of the organic cation tetraethylammonium (TEA) over that shown by vesicles prepared from the drug-sensitive parental line Cl 1D. An outwardly directed proton gradient stimulated TEA and cimetidine uptake by renal brush border membrane vesicles (BBMV) but this gradient did not enhance the uptake of these organic cations into Cl 1D/VCR vesicles. Vinblastine uptake was unaffected by the proton gradient in either vesicle preparation. An outwardly directed gradient of TEA enhanced the uptake of TEA into renal BBMV but did not do so in the case of Cl 1D/VCR vesicles. These data indicate that P-glycoprotein, which is normally energized by ATP hydrolysis, is incapable of catalyzing organic cation/proton exchange or organic cation/organic cation exchange, properties of the organic cation carrier of renal proximal tubule BBMV. The MDR substrates and modulators inhibited the uptake of vinblastine and cimetidine by Cl 1D/VCR vesicles and the uptake of cimetidine and TEA by renal BBMV. Several organic cations studied inhibited TEA and cimetidine uptake by renal BBMV but did not inhibit the uptake of vinblastine and cimetidine by Cl 1D/VCR vesicles.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:P-glycoprotein and organic cation secretion by the mammalian kidney. 791 80

The ability of several Ca(2+)-entry blockers, neuroleptics and local anaesthetics to depress the P-glycoprotein-mediated resistance to vincristine was studied in vitro using the L1210/VCR cell line. This cell line was obtained by long-term adaptation of the L1210 mouse leukaemic cell line on vincristine and showed an overexpression of P-glycoprotein and accompanying multidrug resistance (MDR) which was defined as a cell resistance to several cytostatics such as vincristine, vinblastine and actinomycin D. Efficiency of the drugs applied to reverse this resistance was as follows: for Ca(2+)-entry blockers: verapamil (VER) > or = galopamil (GAL) > flunarizine (FLU) >> diltiazem (DIL) > nimodipine (NIM) > or = nifedipine (NIM); for neuroleptics: trifluoperazine (TFP) > chlorpromazine (CHP) > thioridazine (TRD) > perphenazine (PER); for local anaesthetics: carbanilate-Ca7 > cinchocaine (CIN) >> carbanilate-Ca3 > articaine (ART) > carbanilate CAO > lidocaine (LID). Quaternary cabanilate derivatives (Ca7Q and Ca3Q) with permanent positive charge were found to be unable to reverse the vincristine resistance of L1210/VCR cells. No reasonable correlation between the ability of calcium-entry blockers (DIL, VER, GAL, NIF, NIM and FLU) to reduce the viability of L1210/VCR cells growing in the medium supplemented with vincristine and their reported affinity to the L-type of calcium channel was observed. On the other hand, significant positive correlations were observed between both the inhibitory action of local anaesthetics on propagation of action potential in rat sciatic nerve and the ability of drugs to interact with calmodulin and the ability of the respective drug to reverse the resistance of L1210 cells to vincristine.
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PMID:Reversal effects of several Ca(2+)-entry blockers, neuroleptics and local anaesthetics on P-glycoprotein-mediated vincristine resistance of L1210/VCR mouse leukaemic cell line. 792 90

Fifteen samples from 11 patients suffering from chronic lymphocytic leukaemia (CLL; 5 untreated, 6 chemotherapeutically treated) were analysed for their individual gene expression of the multidrug resistance (MDR) associated genes encoding mdr1/P-glycoprotein, mrp, and topoisomerase II alpha/beta-isoenzymes by a complementary DNA polymerase chain reaction (cDNA-PCR) approach. The expression of glyceraldehyde-3-phosphate dehydrogenase (gapdh) served as standard. Thereby, we generally found high mdr1- and mrp-, but low topoisomerase II alpha-mRNA levels. While mdr1 levels of the CLL samples were mostly found to be in the range of values measured in the T-lymphoblastoid, P-glycoprotein MDR cell line CCRF VCR 100, mrp levels were usually found to be 2-4-fold higher compared therewith. This might represent a multifactorial MDR in CLL. In contrast to the low or even absent topoisomerase II alpha gene expression, however, the expression of the topoisomerase II beta gene was generally high in the CLL lymphocytes exceeding the value observed in the cell line CCRF VCR 100 up to 5-fold. mdr1 gene expression correlated significantly with mrp gene expression in samples from patients having received chemotherapy (rs = 0.5833, P < 0.05, n = 10). In two patients the follow-up analysis revealed combined increases in mdr1- and mrp-gene expression levels in the course of the disease.
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PMID:High mdr1- and mrp-, but low topoisomerase II alpha-gene expression in B-cell chronic lymphocytic leukaemias. 795 50

A multidrug-resistant (mdr) clone of human cancer KB cells was isolated by stepwise selection on exposure to increasing doses of vincristine. The final clone, KBv200, obtained after ethylmethane sulfonate (EMS) mutagenesis showed 175-fold higher resistance to vincristine than did KB cells. The cells were also cross-resistant to taxol, colchicine and adriamycin. Cellular accumulation of vincristine in KBv200 was decreased to less than one-fifth of that in KB. To determine the presence of mdr 1 mRNA in KBv200 and KB, total cellular RNAs from each cell line were analyzed by means of slot blot hybridization. The result showed that the mdr 1 gene had been highly expressed in KBv200. In addition, verapamil, a calcium channel blockers, was shown to increase VCR accumulation in KBv200 and reverse the vincristine resistance. All these results demonstrate that the mechanism of KBv200 cell resistance to multiple drugs resulted from increased expression of mdr 1 gene and brought about over production of P-glycoprotein and increased the efflux of drugs.
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PMID:[Vincristine-resistant human KB cell line and mechanism of multidrug resistance]. 797 38

Active [3H]vinblastine (VBL) transport (efflux) was documented for inside-out plasma membrane vesicles from murine erythroleukemia cells (MEL/VCR-6) resistant to vinca alkaloids and overexpressing MDR 3 P-glycoprotein (P-gp) 80-fold. Uptake of [3H]VBL at 37 degrees C by these inside-out vesicles, but not rightside-out vesicles or inside-out vesicles from wild-type cells, was obtained in the form of a rapid, initial phase (0-1 min) and a slower, later phase (> 1 min). The rapidity of each phase correlated with relative P-gp content among different MEL/VCR cell lines. The initial MDR-specific phase was temperature- and pH-dependent (optimum at pH 7), osmotically insensitive, and did not require ATP. The second MDR-specific phase was temperature-dependent, osmotically sensitive, and strictly dependent upon the presence of ATP (Km = 0.37 +/- 0.04 mM). Although other triphosphate nucleotides were partially effective in replacing ATP, the nonhydrolyzable analogue ATP gamma S (adenosine 5'-O-(thiotriphosphate)) was ineffective. This time course appears to represent tandem binding of [3H]VBL by P-gp and its mediated transport, with the latter process representing the rate-limiting step. In support of this conclusion, both binding and transport were inhibited by verapamil, quinidine, and reserpine, all known to be inhibitors of photoaffinity labeling of P-gp, but only transport was inhibited by C219 anti-P-gp antibody or orthovanadate. Although the rate of transport of [3H]VBL was 7-7.5-fold lower than the rate of binding (Vmax = 104 +/- 15 pmol/min/mg protein, Kon = 1.5 - 2 x 10(5) mol-1 s-1) to P-gp, each phase exhibited saturation kinetics and values for apparent Km and KD for each process were approximately the same (215 +/- 35 and 195 +/- 30 nM). Intravesicular accumulation of [3H]VBL was almost completely eliminated by high concentrations of nonradioactive VBL, suggesting that simple diffusion does not contribute appreciably to total accumulation of [3H]VBL in this vesicle system. This could be at least partially explained by the fact that these inside-out vesicles under the conditions employed did not maintain a P-gp mediated pH gradient. However, ATP-dependent, intravesicular accumulation of osmotically sensitive [3H]VBL occurred against a substantial permeant concentration gradient in both a time- and concentration-dependent manner consistent with an active, saturable process.
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PMID:Functional studies of P-glycoprotein in inside-out plasma membrane vesicles derived from murine erythroleukemia cells overexpressing MDR 3. Properties and kinetics of the interaction of vinblastine with P-glycoprotein and evidence for its active mediated transport. 798 45

Two multidrug-resistant human leukemic CCRF-CEM sublines (CEM/VCR R and CEM/VLB100) were significantly more resistant to tetracycline, a hydrophilic antibiotic, than parental cells (P < 0.001). Verapamil and cyclosporin A completely reversed tetracycline resistance in CEM/VCR R cells, which also accumulated and retained significantly less [3H]tetracycline than CCRF-CEM cells. Like verapamil, addition of tetracycline to CEM/VCR R cells which had achieved steady-state vincristine levels resulted in augmented vincristine accumulation. [3H]Azidopine photoaffinity labelling of CEM/VCR R membrane proteins was inhibited by tetracycline in a dose-dependent manner. Although drugs associated with the multidrug-resistance phenotype are typically hydrophobic compounds, these data suggest that resistance to tetracycline, despite its hydrophilic nature, is mediated by P-glycoprotein in these cell lines.
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PMID:Resistance to tetracycline, a hydrophilic antibiotic, is mediated by P-glycoprotein in human multidrug-resistant cells. 809 60

The sensitivity to antineoplastic agents of subpopulations of haematopoietic cells during cancer chemotherapy is an open question. The performance of natural killer (NK) cells, possibly assisting the elimination of tumour cells under drug treatment might be of particular interest. We examined the expression of the transmembrane multidrug transporter mdr1/P-glycoprotein in NK-cells (CD56+) enriched from the peripheral blood or the umbilical cord blood from healthy donors by indirect immunocytofluorescence using the monoclonal P-glycoprotein antibody C219 and a polymerase chain reaction (PCR) approach with amplimers specific for the human mdr1 cDNA. As the antibody C219 apparently cross-reacts with the human mdr3 gene product whose functions are as yet unclear we also checked expression of this gene by PCR using mdr3 specific amplimers. Distinct, but rather inhomogeneous mdr1/P-glycoprotein expression was found in NK-cells enriched from the peripheral blood. NK-cells enriched from the umbilical cord blood showed quite strong mdr1 expression levels throughout, exceeding the values found in the moderately multidrug-resistant cell line CCRF VCR 100 which is permanently cultivated in the presence of 100 ng/ml vincristine. Mdr1/P-glycoprotein expression was mirrored by lowered sensitivities of the cultivated NK-cells towards actinomycin D or adriamycin. The drug sensitivity could be modulated by treatment of the cells with the immunosuppressive drug cyclosporin A. Expression of the mdr3 gene was low or absent in all NK-cell samples examined so far.
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PMID:Mdr1/P-glycoprotein expression in natural killer (NK) cells enriched from peripheral or umbilical cord blood. 809 58

The relationship between cell-membrane permeability to vincristine and cholesterol/phospholipid levels was studied in L5178Y murine leukemic lymphoblasts and in 2 multidrug-resistant cell sublines, VCR/P60 and VCR/P200, which expressed increasing levels of vincristine resistance. The uptake of 3H-vincristine was measured in all cell lines and in cholesterol-depleted and -reloaded L5178Y and VCR/P200 cells. The initial rate of drug entry in resistant cells was lower than that measured in the parental cell line and it decreased as the relative resistance increased. An increment of cholesterol content, characterized in resistant cells, was directly proportional to the relative resistance to vincristine. Cholesterol depletion in both sensitive and resistant cells resulted in an increase in the rate of vincristine uptake, which reverted to the respective basal levels when each cell line was cholesterol-reloaded. The rate of drug uptake was inversely correlated with the molar ratio of cholesterol to phospholipids. Although both VCR/P cell sublines, but not the sensitive parental cells, expressed the P-glycoprotein in their plasma membrane, there were no differences in drug efflux and retention between resistant and parental cells. These results indicate that cholesterol modulates the permeation of vincristine through the plasma membrane and strongly suggest that increased levels of cholesterol/phospholipid account for the lower drug accumulation and greater resistance in these multidrug-resistant cells.
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PMID:Role of cell cholesterol in modulating vincristine uptake and resistance. 840 97

Cyclosporin A (CyA) overcomes P-glycoprotein (P-gp) associated multidrug resistance (MDR). P-gp expression is frequently observed among, not only various cancer cells, but also several normal tissues including bone marrow progenitor cells. These findings lead us to examine whether CyA enhances the myelotoxicity of anti-cancer agents. Bone marrow mononuclear cells were incubated with anti-cancer agents (vincristine, VCR; doxorubicin, ADM; etoposide, VP-16; cytarabine, Ara-C; methotrexate, MTX) and a concentration of CyA (0.5, 5.0 micrograms/mL). The methylcellulose assay for granulocyte-macrophage progenitors (CFU-GM) was conducted using the post-treated cells. There was no significant toxicity for marrow CFU-GM formation after 72 h incubation with CyA (84-108% of control). The inhibitory concentration that reduced colonies by 50% (IC50) was 12 nmol/L for VCR, 6 nmol/L for ADM, 220 nmol/L for VP-16, 15 nmol/L for Ara-C and 35 nmol/L for MTX, respectively. For VCR, ADM and VP-16, the number of CFU-GM was unchanged with the addition of CyA at 0.5 microgram/mL concentration. In contrast at 5 micrograms/mL CyA, the number of CFU-GM (% of control) was reduced significantly (P < 0.05 or P < 0.01). With MTX and Ara-C, the number of CFU-GM was unchanged after addition of CyA, even at 5 micrograms/mL concentration. We conclude CyA may therefore enhance cytotoxic drug sensitivity in MDR tumor cells at a clinically achievable concentration (0.5 microgram/mL) without marrow toxicity.
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PMID:Effect of cyclosporin A on human bone marrow granulocyte-macrophage progenitors with anti-cancer agents. 853 88

A reasonably facile and effective procedure is described for the preparation of inside-out plasma membrane vesicles from tumor cells. The method incorporates nitrogen cavitation, optimized with respect to the applied N2 pressure, in the absence of added divalent cations followed by differential centrifugation and discontinuous, sucrose gradient centrifugation. With the three tumor cell types utilized, multidrug-resistant (MEL/VCR-6) and parental (MEL/O) murine erythroleukemia cells and methotrexate-resistant (L1210/R24) L1210 leukemia cells, yields were in the range of 8-12 mg of plasma membrane vesicles/10(10) cells at a purity of 87-94% with average inside-out sidedness among preparations varying from 65 to 93% depending upon the cell type. Inside-out plasma membrane vesicles so derived were capable of sustaining ATP-dependent transport inward of two common antitumor cytotoxic agents, vinblastine and methotrexate. The former was demonstrated with inside-out vesicles from only P-glycoprotein-overexpressing, multidrug-resistant MEL/VCR-6 cells, while the latter was readily demonstrated in inside-out vesicles from all three cell types.
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PMID:Facile preparation of inside-out plasma membrane vesicles from tumor cells for functional studies of pharmacologically relevant translocating ATPases. 857 99


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