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)

Anthracycline accumulation was evaluated by flow cytometry or radiolabeled drug assays in cells and cytoplasts (enucleated cells) prepared from parental and multidrug-resistant human K562 leukemia cells. Treatment with energy inhibitors, such as dinitrophenol (DNP) or sodium azide/deoxyglucose, led to a marked decrease in daunorubicin accumulation in parental cells and cytoplasts. Another ionophore, monensin, also caused a significant decrease in daunorubicin accumulation; however, ATPase inhibitors ouabain, vanadate, and N-ethylamaleimide had little or no effect. The lysosomatropic agents chloroquine and methylamine caused a moderate decrease in anthracycline accumulation. Fluorescence microscopy showed that the DNP-sensitive daunorubicin uptake occurred in a nonnuclear subcellular compartment. Studies using increasing daunorubicin concentrations demonstrated fluorescence quenching that occurred in the nonnuclear, DNP-sensitive compartment. The effect of inhibitors on the accumulation of rhodamine 123 and acridine orange strongly implicated lysosomes as the principal compartment of this inhibitable daunorubicin accumulation. Cytoplasts from P-glycoprotein containing multidrug-resistant K562 cells demonstrated a verapamil-reversible, decreased daunorubicin accumulation that was observed in resistant whole cells. Verapamil pretreatment of cytoplasts from resistant cells revealed the subcellular DNP-sensitive uptake present in parental cytoplasts. These studies demonstrate that cytoplasts are an effective means to study drug transport in mammalian cells without nuclear drug binding. Parental K562 cells and cytoplasts exhibit an energy-dependent accumulation of daunorubicin into cytoplasmic organelles that is also present in resistant cells and cytoplasts when P-glycoprotein mediated efflux is inhibited.
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PMID:Energy-dependent accumulation of daunorubicin into subcellular compartments of human leukemia cells and cytoplasts. 135 Feb 80

In an attempt to characterize and overcome tumor cell resistance to amsacrine (m-AMSA), we studied the structure-activity relationships for amsacrine and seven of its analogs. Using the human leukemic cell line, CCRF-CEM, and its derivatives that express either P-glycoprotein (Pgp)-associated multidrug resistance (MDR) (CEM/VLB100) or altered topoisomerase II-associated MDR (at-MDR) (CEM/VM-1), we assessed antitumor effects of these drugs in a 48-hr growth inhibition assay. We also measured drug-topoisomerase II interactions in an intact cell assay that permits quantitation of drug-stabilized DNA-topoisomerase II complexes. We found that among the tested compounds, amsacrine has an intermediate effect on cell growth in all three cell lines. The CEM/VM-1 cells were 8.6-fold cross-resistant to m-AMSA, and the cross-resistance to the analogs was from 3.0- to 10.5-fold. In the CEM/VLB100 cells, the resistance pattern was different: several analogs, including amsacrine, showed little or no cross-resistance (0.5- to 2.8-fold), whereas for those compounds with substituents at position 3 on the acridine ring, resistance was relatively higher (9.9- or 16.2-fold). Substituents at this position substantially decrease the lipophilicity of the two compounds examined, probably because they both contain amino groups that would be charged at physiologic pH. Compound 12489, having a 1'-NHSO2C6H4NH2 substituent, was very potent in the three cell lines, showing only a slightly higher IC50 value in the CEM/VM-1 line and a lower IC50 value in the CEM/VLB100 and in the CEM cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Structure-activity studies of amsacrine analogs in drug resistant human leukemia cell lines expressing either altered DNA topoisomerase II or P-glycoprotein. 136 24

This study explores properties of P-glycoprotein dependent membrane transport in rat liver with the use of acridine orange as the substrate. We studied the biliary secretion of the dye, its binding to canalicular membrane P-glycoprotein, and effects of the inhibitor cyclosporin A: acridine orange is excreted into bile together with less hydrophobic and glucuronidated metabolites. Cyclosporin A inhibited both the secretion of acridine orange and of its metabolites. In TR- animals, a rat strain that is deficient of the canalicular multi-specific organic anion transport system, non-metabolized acridine orange is the predominant species in bile and its secretion is also inhibited by cyclosporin A. Binding of acridine orange to liver P-glycoprotein was analyzed by photoaffinity labeling with azidopine, a substrate of P-glycoprotein dependent transport in multi-drug resistant tumor cells. Labeling of the immunoprecipitated P-glycoprotein was inhibited by acridine orange, verapamil, and by cyclosporin A. The results show that biliary secretion of acridine orange is highly analogous to P-glycoprotein mediated membrane drug transport in tumor cells that exhibit multi-drug resistance.
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PMID:Bile canalicular cationic dye secretion as a model for P-glycoprotein mediated transport. 791 84

Resistance of tumor cells to doxorubicin is a multifactorial phenomenon. In the present investigation, the ability of resistance modifiers against different resistance mechanisms was analysed. Substances which block P-glycoprotein (P-170) function circumvented resistance of doxorubicin-resistant sarcoma 180 (S180) cells completely (verapamil, thioridazine) or partially (hycanthone), whereas inhibitors of glutathione S-transferase (ethacrynic acid, N-ethylmaleimide, buthionine sulfoximine), and protein kinase C (staurosporine, acridine orange) caused only a partial reversion of resistance. In contrast, an inhibitor of alkaline phosphatase (levamisole) did not overcome doxorubicin-resistance. These results indicate that P-glycoprotein blockers might be more effective to modulate doxorubicin-resistance of S180 cells as compared to other modifiers. Further investigations using other MDR cell lines are required to clarify the generality of these findings.
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PMID:Reversal of doxorubicin-resistance in sarcoma 180 tumor cells by inhibition of different resistance mechanisms. 810 93

The successful treatment of cancer requires the identification of new drugs with novel actions. N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride (DACA) is a topoisomerase II-targeted antitumour drug with curative activity against murine Lewis lung carcinoma. DACA was assessed for novel patterns of growth inhibition using normal and multidrug-resistant human cell lines. Cells were cultured in 96-well microtitre trays and tested against DACA and related topoisomerase-directed drugs, including amsacrine, etoposide and doxorubicin, and drug concentrations for 50% growth inhibition (IC50 or GI50 values) were determined. In a series of Jurkat leukaemia lines characterised as exhibiting atypical multidrug resistance, DACA was to a large extent capable of overcoming multidrug resistance exhibited towards the other topoisomerase-directed agents. DACA was also tested against the National Cancer Institute 60-tumour-specific cell-line panel (GI50 values ranging from 420 to 5,400 nM; mean, 2,100 nM) and against a series of primary cultures of surgically excised melanomas (IC50 values ranging from 60 to 1,600 nM; mean, 590 nM). DELTA values (deviations of logarithmic IC50 or GI50 values from the mean) were calculated and compared by correlation analysis. The standard deviation of DELTA values was found to be lower for DACA than for the other topoisomerase II-directed drugs amsacrine, etoposide, doxorubicin and mitozantrone in both the cell lines and the primary cultures. These lower standard deviations appear to have resulted from the reduced susceptibility of DACA to both P-glycoprotein- and topoisomerase II-mediated multidrug-resistance mechanisms occurring naturally in cell lines and primary cultures.
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PMID:In vitro assessment of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide, a DNA-intercalating antitumour drug with reduced sensitivity to multidrug resistance. 838 21

N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]- phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) has been selected from a chemical program aimed at identifying an optimized inhibitor of multidrug resistance (MDR). The potency of GF120918 is assessed by dose-dependent sensitization of CHRC5, OV1/DXR and MCF7/ADR cells to the cytotoxicity of doxorubicin and vincristine respectively: GF120918 fully reverses multidrug resistance at 0.05 to 0.1 microM and is half maximally active at 0.02 microM. The spectrum of drugs sensitized by GF120918 coincides with those having the classical MDR phenotype. In CHRC5 cells, 0.01-0.1 microM GF120918 enhances the uptake of [3H]daunorubicin and blocks the efflux from preloaded cells. It is also shown that GF120918 is still active several hours after being taken away from the culture medium showing that it is not, like verapamil, effluxed rapidly by P-glycoprotein. GF120918 effectively competes with [3H]azidopine for binding P-glycoprotein, pointing to this transport membrane protein as its likely site of action. After i.v. administration to mice, GF120918 penetrates thoroughly various organs that have a tissue level/blood level ratio above 10. It is eliminated from organs and blood with a half-time of approximately 2.7 h. It is well absorbed after p.o. administration. In mice implanted i.p. with the MDR P388/Dox tumor, a single i.v. or p.o. dose of GF120918 restores sensitivity of the tumor to a single i.p. dose (5 mg/kg) of doxorubicin administered 1 h later. A statistically significant effect is observed at 1 mg/kg GF120918 i.v. and maximal effect is reached at 5 mg/kg. Similarly, whereas neither drug alone is effective, GF120918 (10 mg/kg i.p.) associated with doxorubicin (5 mg/kg i.p.) inhibits the growth of the moderately MDR C26 tumor implanted s.c. as assessed by tumor size at day 19. GF120918 does not modify significantly the distribution or the elimination of doxorubicin in mice ruling out the possibility that the antitumor effects seen might be explained by pharmacokinetic interactions.
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PMID:In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative. 840 33

P-glycoprotein (P-gp), the multidrug resistance (MDR) gene product, is exclusively located on the canalicular membrane of hepatocytes. Recent studies using isolated rat canalicular liver plasma membrane (cLPM) vesicles indicate that daunomycin (DNM) is a substrate for the ATP-dependent P-gp efflux system in the rat liver. The isoforms of P-gp present in cLPM and in cancer cell lines differ in that the major form present in the liver represents the gene product of mdr2 in mice (MDR3 in humans; class III) while the isoform of P-gp in cancer cells is the gene product of mdr1 in mice (MDR1 in humans, class I). The objective of this study was to examine the inhibitory effects of various organic compounds, most of which have been studied previously in MDR cancer cells, on P-gp-mediated [3H]DNM uptake into cLPM. Also, the stereospecificity of P-gp for its substrates was investigated by comparing the inhibitory effects of the enantiomers and the racemic mixtures of verapamil and propranolol. DNM exhibited ATP-dependent active transport into rat liver cLPM with a Km of 26.8 +/- 13.4 microM and a Vmax of 4.9 +/- 0.8 nmol/45 s/mg of protein (n = 4). ADP, AMP, and a nonhydrolyzable ATP analogue did not increase DNM transport over the control value. Thirty-one potential inhibitors were examined; only acridine orange, doxorubicin, verapamil, propranolol, phosphatidylcholine, beta-estradiol glucuronide, and DNM itself showed statistically significant inhibition of [3H]DNM uptake into cLPM. These results suggest that only a limited number of substrates bind to or are transported across the hepatic canalicular membrane via P-gp. Phosphatidylcholine, a substrate for the gene product of the class III P-gp gene, produced significant inhibition of [3H]DNM transport (30.6% at a 10-fold-higher substrate concentration), suggesting that transport may be mediated, at least in part, by this P-gp gene product. There were no statistically significant differences in the inhibitory effects of the enantiomers and racemate of verapamil on [3H]DNM transport into cLPM, but the enantiomers of propranolol exhibited stereospecific inhibition of DNM transport. (R)-(+)-Propranolol produced a statistically significant inhibition of [3H]DNM transport similar to that observed with the racemic mixture, while (S)(-)-propranolol showed no inhibition. These findings suggest that bile canalicular P-gp may exhibit stereospecificity of binding or transport for its substrates.
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PMID:Inhibitors of P-glycoprotein-mediated daunomycin transport in rat liver canalicular membrane vesicles. 887 82

Resistance to chemotherapy in multiple myeloma (MM) and acute myeloid leukemia (AML) is frequently caused by multiple drug resistance (MDR), characterized by a decreased intracellular drug accumulation. MDR is associated with expression of P-glycoprotein (P-gp). GF120918, an acridine derivative, enhances doxorubicin cell kill in resistant cell lines. In this study, the effect of GF120918 on MDR cell lines and fresh human leukemia and myeloma cells was investigated. The reduced net intracellular rhodamine-123 (Rh-123) accumulation in the MDR cell lines RPMI 8226/Dox1, /Dox4, /Dox6 and /Dox40 as compared with wild-type 8226/S was reversed by GF120918 (0.5-1.0 microM), and complete inhibition of rhodamine efflux was achieved at 1-2 microM. This effect could be maintained in drug-free medium for at least 5 h. GF120918 reversal activity was significantly reduced with a maximum of 70% in cells incubated with up to 100% serum. GF120918 significantly augmented Rh-123 accumulation in vitro in CD34-positive acute leukemia (AML) blasts and CD38-positive myeloma (MM) plasma cells obtained from 11/27 de novo AML and 2/12 refractory MM patients. A significant correlation was observed between a high P-gp expression and GF120918 induced Rh-123 reversal (P=0.0001). Using a MRK16/IgG2a ratio > or = 1.1, samples could be identified with a high probability of GF120918 reversal of Rh-123 accumulation. In conclusion, GF120918 is a promising MDR reversal agent which is active at clinically achievable serum concentrations.
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PMID:In vitro effect of GF120918, a novel reversal agent of multidrug resistance, on acute leukemia and multiple myeloma cells. 894 33

The effectiveness of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) relative to that of amsacrine, idarubicin, daunorubicin and paclitaxel against three different forms of multidrug resistance (MDR) was determined using two sublines of the CCRF-CEM human leukaemia cell line, the P-glyco-protein-expressing CEM/VLB100 subline and the MRP-expressing CEM/E1000 subline, and two extended-MDR sublines of the HL60 human leukaemia cell line, HL60/E8 and HL60/V8. DACA was effective against P-glycoprotein-mediated MDR and MRP-mediated MDR, whereas the extended-MDR phenotype showed only low levels of resistance (< 2-fold) to DACA. In comparison, idarubicin was ineffective against the MRP and extended-MDR phenotypes. Repeated exposure of the K562 human leukaemia cell line to DACA (55, 546 or 1092 nM for 3 days over 10 weeks) did not result in the development of any significant drug resistance. We conclude that DACA has the potential to treat refractory leukaemia.
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PMID:The potential of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide to circumvent three multidrug-resistance phenotypes in vitro. 905 56

The acridone carboxamide derivative GG918 (N-{4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-pheny l}-9,10dihydro-5-methoxy-9-oxo-4-acridine carboxamide) is a potent inhibitor of MDR1 P-glycoprotein-mediated multidrug resistance. Direct measurements of ATP-dependent MDR1 P-glycoprotein-mediated transport in plasma membrane vesicles from human and rat hepatocyte canalicular membranes indicated 50% inhibition at GG918 concentrations between 8 nM and 80 nM using N-pentyl-[3H]quinidinium, ['4C]doxorubicin and [3H]daunorubicin as substrates. The inhibition constant K for GG918 was 35 nM in rat hepatocyte canalicular membrane vesicles with [3H]daunorubicin as the substrate. Photoaffinity labelling of canalicular and recombinant rat Mdr1b P-glycoprotein by [3H]azidopine was suppressed by 10 muM and 40 muM GG918. The high selectivity of GG918-induced inhibition was demonstrated in canalicular membrane vesicles and by analysis of the hepatobiliary elimination in rats using [3H]daunorubicin, [3H]taurocholate and [3H]cysteinyl leukotrienes as substrates for three distinct ATP-dependent export pumps. Almost complete inhibition of [3H]daunorubicin transport was observed at GG918 concentrations that did not affect the other hepatocyte canalicular export pumps. The high potency and selectivity of GG918 for the inhibition of human MDR1 and rat Mdr1b P-glycoprotein may serve to interfere with this type of multidrug resistance and provides a tool for studies on the function of these ATP-dependent transport proteins.
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PMID:Selective inhibition of MDR1 P-glycoprotein-mediated transport by the acridone carboxamide derivative GG918. 1009 36


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