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)

Leishmania tarentolae cells selected for resistance to the oxyanions pentavalent or trivalent antimonials or to trivalent arsenicals exhibited cross-resistance to the other oxyanions. The basis for resistance in these mutants was studied by transport experiments using radioactive arsenite. All mutants exhibiting high level resistance to arsenite showed a marked decrease in the steady-state accumulation of arsenite. Decreased accumulation was also observed in antimonials-resistant mutants cross-resistant to various concentrations of arsenite. Cells depleted of endogenous energy reserves with metabolic inhibitors were loaded with radioactive arsenite; following addition of glucose, rapid efflux of arsenite was observed from arsenite mutant cells. Mutants resistant to high levels of arsenicals exhibited amplification of the P-glycoprotein related gene ltpgpA or of a linear amplicon of unknown function. However, the efflux-mediated arsenite resistance did not correlate with the amplification of the ltpgpA gene or with the presence of the linear amplicon. The calcium channel blocker verapamil and arsenite act in synergy in cells exhibiting the efflux system. Overall the oxyanion efflux system in Leishmania shares several properties with other resistance efflux systems mediated by transporters.
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PMID:High level arsenite resistance in Leishmania tarentolae is mediated by an active extrusion system. 783 83

P-glycoprotein plays a key role in the mechanisms of multidrug resistance in experimental tumors as well as in clinical tumors both in acquired and intrinsic-type resistance. Thus the therapeutic approaches targeting P-glycoprotein would provide benefits in eradication of drug-resistant tumor cells, although some potential problems concerning side effects still remain to be studied. Practical approaches to overcoming multidrug resistance by targeting the P-glycoprotein would be (1) to use antibodies against P-glycoprotein; and (2) to use agents, including calcium channel blocker-related agents and membrane-modifying agents, that interact with P-glycoprotein. These therapeutic approaches will be discussed in the symposium.
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PMID:[Development of drugs to overcome drug resistance--basic approaches]. 788 Jan 7

The purpose of this study was to identify calcium channel and calmodulin antagonists effective in increasing the cytotoxic effects of several chemotherapeutic drugs against UV-2237 murine fibrosarcoma MDR cells. Among 8 compounds tested at nontoxic concentrations, flupentixol, a piperazine-substituted thioxanthene, was the most potent in enhancing the cytotoxicity of anticancer drugs commonly associated with the multidrug resistant (MDR) phenotype, such as Adriamycin, actinomycin D, vinblastine, and vincristine, but not 5-fluorouracil, a drug usually unaffected by MDR. The chemosensitizing effects of flupentixol were produced by increasing intracellular drug accumulation via a mechanism unrelated to the binding of the plasma membrane P-glycoprotein.
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PMID:Reversal of multidrug resistance in murine fibrosarcoma cells by thioxanthene flupentixol. 789 37

Multidrug-resistant tumor cells can be resensitized by combined application of the selecting cytostatic drug and a chemosensitizer, such as cyclosporin A (CsA) or a calcium channel blocker. Since clinical trials on the circumvention of multidrug resistance (MDR) with chemosensitizers report disparate results, we investigated whether tumor cells of the MDR phenotype can develop additional resistance to the cytostatic chemosensitizer combination. Thus, the Adriamycin(ADR)-selected, P-glycoprotein-positive MDR Friend leukemia cell line F4-6RADR was exposed to stepwise increased concentrations of CsA at a constant level of 0.05 microgram/ml ADR. The initial CsA concentration (plus 0.05 microgram/ml ADR) to inhibit cell growth of F4-6RADR cells by 50% (IC50) was 0.04 microgram/ml. By continuous incubation for more than 6 months, the IC50 for CsA (at constant ADR) was elevated to 3.6 micrograms/ml (90-fold), thus generating the variant F4-6RADR-CsA. The F4-6RADR-CsA cells were cross-resistant for cyclosporin H (CsH), a non-immunosuppressive derivative of CsA. As shown by immunocytochemistry as well as by the polymerase chain reaction and by Western blotting including densitometry, P-glycoprotein was preserved in the F4-6RADR-CsA variant and was expressed at a 4-fold higher level than in F4-6RADR cells. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis analysis could detect no new proteins in F4-6RADR-CsA as compared to F4-6RADR. Interestingly, resistance of F4-6RADR-CsA cells remained reversible for the calcium antagonists verapamil and dihydropyridine B859-35 (dexniguldipine-HCl), indicating that CsA and these compounds interfere with the P glycoprotein function by different pharmacodynamic mechanisms. Transport studies with [14C]ADR, performed in the presence and absence of chemosensitizers, confirmed the good correlation of P-glycoprotein function with the pattern of resistance found in proliferation assays. Cellular accumulation of [3H]cyclosporin was reduced to 71% of that of the F4-6 controls in F4-6RADR-CsA cells, but remained at the level of controls in F4-6RADR cells. Results indicate that increased amounts of the P-glycoprotein--besides other, perhaps more important mechanisms that are as yet unknown--partially mediate CsA resistance in F4-6RADR-CsA cells. We have designated this new form of resistance "secondary combined resistance" (SCR). The results suggest that at least some clinical cases of insensitivity to chemosensitizers or of relapse after reversing therapy could be explained by SCR, and that resensitizing treatment of tumor patients should be based on the consideration of several chemosensitizers of different pharmacodynamics.
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PMID:Secondary combined resistance to the multidrug-resistance-reversing activity of cyclosporin A in the cell line F4-6RADR-CsA. 790 33

Multidrug-resistance (MDR) is a cellular mechanism, which in certain tumors reduces the chemosensitivity of cells to a characteristic group of structural different cytostatic drugs, as anthracyclines, Vinca alkaloids and others, and correlates with a unfavourable clinical prognosis. In MDR-cells the intracellular concentration of cytostatic drugs is reduced due to the action of the mdr-1-gene-encoded P-glycoprotein (P-gp/gp 170), which functions as drug efflux pump with broad substrate specificity. Many calcium channel blockers of all subclasses (phenylalkylamine, dihydropyridine and benzothiazepine type) and other calcium antagonists inhibit the P-gp-mediated drug efflux and represent modulators of MDR (resistance modifiers, chemosensitizers). Since the sensitized tumor cells express no voltage-gated calcium channels, the induction of changes in intracellular free calcium showed no effect on MDR and the MDR-activity of antagonists is not correlated with their cardiovascular effects, the chemosensitization by these drugs is independent from their action on calcium channels and Ca(++)-regulation. Photoaffinity labelling with reactive derivatives proved the direct competitive interaction of calcium antagonists with the binding site of P-gp for cytostatic drugs as mechanism of action. The MDR-modulation of the doxorubicin or Vinca alkaloid resistance of tumor cells in vitro by verapamil and other calcium channel blockers was confirmed in vivo as increased survival length in mice with tumor transplants in combination with cytostatic therapy. The clinical application of calcium antagonists is limited by their severe cardiovascular side effects associated with the high concentrations required for successful reversal of MDR.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Calcium antagonists as modulators of multi-drug resistant tumor cells]. 790 28

Yoshida rat ascites hepatoma (AH) has several cell lines with a characteristic sensitivity to antitumor drugs. AH66 cells overexpressed 160-170 kDa P-glycoprotein (P-gp) in the membrane and glutathione-S-transferase placental form (GST-P) in the cytosol. AH44 cells did not express P-gp but contained GST-P isozyme, while normal rat liver had GST-(1,2) and-(3,4) classes. AH44 and AH66 cells were more resistant to chlorambucil (CLB) than AH66F cells, which are a variant cell line derived from AH66 cells and lacked both proteins. CLB-resistant AH44 and AH66 cells contained a high amount of glutathione (GSH) and higher GST activity than AH66F cells. Ethacrynic acid, a GST-P inhibitor, and buthionine sulfoximine, a GSH biosynthesis inhibitor, significantly decreased the CBL resistance of AH44 and AH66 cells without influencing the sensitivity of AH66F cells. The CLB resistance of these cell lines were hardly influenced by verapamil, a calcium channel blocker with P-gp antagonistic action, which significantly decreased the vinblastine resistance of AH66 cells. This study indicates that AH66 cells showed multiple drug resistance dependent on P-gp and GST-P isozyme and that the AH44 cell line was CLB resistant through the GSH/GST-P detoxification system. These hepatomas are useful for investigation of the drug resistance of hepatic carcinomas and development of counteracting drugs.
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PMID:Glutathione-S-transferase P-form dependent chlorambucil resistance in Yoshida rat ascites hepatoma cell lines. 791 Jan 11

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

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

Natural killer (NK) cells have been reported recently to be the highest in expressing multidrug resistance (MDR) P-glycoprotein among normal mature lymphoid cells. Using a cultured NK cell-rich population, we have examined the expression and function of P-glycoprotein, in particular its role in NK cell-mediated cytotoxicity, by employing two MDR-reversing agents (nicardipine and AHC-52, a nicardipine analog almost devoid of calcium channel blocking activity) and monoclonal antibody against P-glycoprotein (MRK-16). The expression of P-glycoprotein was detected by flow cytometry and polymerase chain reaction of reverse transcribed mRNA. P-glycoprotein was functional in terms of rhodamine dye excretion and its susceptibility to the MDR-reversing agents. Since the concentration of nicardipine required for 50% inhibition (IC50) of rhodamine dye excretion (2 microM) was close to that of AHC-52 (5 microM), it was suggested that their inhibitory effects were not due to calcium channel blocking activity, and that ACH-52 is a selective inhibitor for P-glycoprotein. The IC50 of nicardipine for NK cell-mediated cytotoxicity (33 microM) was also close to that of AHC-52 (26 microM), indicating that P-glycoprotein is involved in NK cell-mediated cytotoxicity. In support of this, MRK16 inhibited NK cell-mediated cytotoxicity in a concentration-dependent manner. Both binding of target cells to NK cells and post-binding events were affected by AHC-52, suggesting that P-glycoprotein is involved in several steps in NK cell-mediated cytotoxicity.
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PMID:Expression and function of multidrug resistance P-glycoprotein in a cultured natural killer cell-rich population revealed by MRK16 monoclonal antibody and AHC-52. 798 Jun 29

We observed increased levels of mdr-1 mRNA and its protein product P-glycoprotein (Pgp) in the human colon carcinoma cell line, LS 180, and its drug-resistant sublines, LS 180-Ad50 and LS 180-Vb2, after treatment with the Pgp antagonists, verapamil, nifedipine, and cyclosporin A. Increases in mdr-1 RNA were observed within 8 h of the addition of the Pgp antagonists and continued to rise over time. Peak levels were attained after several weeks and were sustained for the duration of treatment up to several months, with a rapid decline in mdr-1 mRNA levels after removal of the Pgp antagonist. Corresponding changes in Pgp were demonstrated with addition and removal of the Pgp antagonists. Increased mdr-1 mRNA was also seen with two other calcium channel blockers, nicardipine and diltiazem, but not with the Pgp antagonists, quinidine and chlorpromazine. Treatment with verapamil or nifedipine was associated with electron microscopic changes consistent with increased differentiation and resulted in increased carcinoembryonic antigen expression, suggesting that the increase in mdr-1 expression was associated with the process of differentiation. Nuclear runoff experiments and inhibition of new RNA synthesis with actinomycin D treatment failed to detect an increase in mdr-1 transcription or stabilization of the mdr-1 mRNA suggesting that the effect of these agents is mediated posttranscriptionally within the nucleus.
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PMID:Increased mdr-1/P-glycoprotein expression after treatment of human colon carcinoma cells with P-glycoprotein antagonists. 809 79


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