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)

We studied the effect of thioacridine derivatives on the function of P-glycoprotein in MDR mouse T-lymphoma cell line L5178 and in MDR human leukemia cell line K562/ADR by rhodamine 123 uptake assay. The effect of some selected thioacridines was also investigated on the expression of the mdr1 gene. Expression was analysed by RT-PCR. Two compounds: 3-amino-9-thio-(4'-nitrobenzyl)acridinone and 2,7-dimethoxy-9-thio-(2'-diethylaminoethyl) acridinone were able to block the function of the P-gp, and also to decrease significantly mdr1 gene expression. Because these two derivatives exert their positive effects as reversing agents they could be potential candidate anticancer agents for further investigation. The thioacridines, which do not affect P-gp function, do not affect or increase the expression of mdr1 gene. Our results showed the structure-activity relationships of these compounds, providing a direction for the development of new, more active compounds.
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PMID:Effect of new thioacridine derivatives on P-gp function and on mdr1 gene expression. 971 9

Toremifene (TOR) is a new antiestrogenic agent, a triphenylethylene derivative that was developed as an alternative to tamoxifene (TAM). TOR has been observed to be more effective than TAM with milder toxicity at high doses. We examined the in vitro combination-effect of TOR with cyclophosphamide, adriamycin, 5-fluorouracil and three drug mixture (CAF) on the growth of various human mammary carcinomas. The combination shows a semi-additive or additive growth inhibitory effect on all estrogen positive cells used here except one cell line. In particular, the additive or synergic combination-effect was observed on TAM resistant cells. Furthermore, TOR exhibits a chemosensitizing activity in ADR-resistant cells by expressing P-glycoprotein coded by MDR-1 (multidrug resistance gene). The chemosensitizing activity is dose-dependent of TOR. As described above, the combination of TOR with CAF shows more than a semi-additive effect in this experiment. In conclusion, the addition of high-dose TOR to CAF therapy might be useful for advanced/recurrent breast cancer.
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PMID:[The in vitro combination-effect of toremifene with CAF (cyclophosphamide, adriamycin, 5-fluorouracil) on growth of various human mammary carcinomas]. 972 52

Vinflunine (VFL) is a novel derivative of vinorelbine (NVB, Navelbine), which has shown markedly superior antitumor activity to NVB, in various experimental animal models. To establish whether this new Vinca alkaloid participates in P-glycoprotein (Pgp)-mediated multidrug resistance (MDR), VFL-resistant murine P388 cells (P388/VFL) were established in vivo and used in conjunction with the well established MDR P388/ADR subline, to define the in vivo resistance profile for VFL. P388/VFL cells proved cross-resistant to drugs implicated in MDR (other Vinca alkaloids, doxorubicin, etoposide), but not to campothecin or cisplatin and showed an increased expression of Pgp, without any detectable alterations in topoisomerase II or in glutathione metabolism. The P388/ADR cells proved cross-resistant to VFL both in vivo and in vitro, and this VFL resistance was efficiently modulated by verapamil in vitro. Cellular transport experiments with tritiated-VFL revealed differential uptake by P388 sensitive and P388/ADR resistant cells, comparable with data obtained using tritiated-NVB. In various in vitro models of human MDR tumor cells, whilst full sensitivity was retained in cells expressing alternative non-Pgp-mediated MDR mechanisms, cross resistance was identified in Pgp-overexpressing cells. Differences were, however, noted in terms of the drug resistance profiles relative to the other Vinca, with tumor cell lines proving generally least cross-resistant to VFL. Overall, these results suggest that VFL, like other Vinca alkaloids, participates in Pgp-mediated MDR, with tumor cells selected for resistance to VFL overexpressing Pgp, yet MDR tumor cell lines proved generally less cross resistant to VFL relative to the other Vinca alkaloids.
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PMID:Vinflunine (20',20'-difluoro-3',4'-dihydrovinorelbine), a novel Vinca alkaloid, which participates in P-glycoprotein (Pgp)-mediated multidrug resistance in vivo and in vitro. 974 May 39

N-(2-Chloroethyl)-N-nitrosoureidodaunorubicin (AD 312), a novel semisynthetic compound with combined anthracycline and nitrosourea alkylating functionalities, circumvents resistance conferred by either reduced DNA topoisomerase II (topo II) or increased P-glycoprotein expression with less myelosuppression and cardiotoxicity than adriamycin (doxorubicin; ADR). Cellular resistance to AD 312 could arise from a novel mechanism that confers resistance to both functions simultaneously, or one or more mechanisms common to anthracyclines and/or alkylating agents. The mechanism contributing to AD 312 resistance was investigated following selection of AD 312-resistant murine J774.2 macrophage-like cells and human NCI-H460 non-small-cell lung carcinoma cells. Murine J/312-400 (> 4.7-fold) and human H/312-40 cells (6.3-fold) were cross-resistant to topo II inhibitors (ADR, teniposide, etoposide) and nitrosoureas (carmustine, lomustine) but remained sensitive to vinblastine, colchicine, and camptothecin. There was approximately a twofold decrease in topo II decatenation activity and protein. Decreased net intracellular drug accumulation was not observed. There were no increases in glutathione content or glutathione-S-transferase activity. Increased O6-methylguanine-DNA methyltransferase (MGMT) activity (2.3-fold) was detected in J/312-400, and AD 312 resistance was partially reversed by O6-benzylguanine, a potent inhibitor of MGMT activity. The results suggest that AD 312 resistance arose through selective pressure by both cytotoxic functions in a serial manner.
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PMID:Cellular resistance against the novel hybrid anthracycline N-(2-chloroethyl)-N-nitrosoureidodaunorubicin (AD 312) is mediated by combined altered topoisomerase II and O6-methylguanine-DNA methyltransferase activities. 977 92

Multidrug resistance (MDR) is considered multifactorial and has been associated with overexpression of the multidrug resistance protein (MRP). However, effective compounds for reversal of MRP-related MDR are limited. In the present study, the modulatory activity of the novel pyridine analogue PAK-104P on MRP-mediated resistance to doxorubicin and paclitaxel was investigated in two doxorubicin-selected human tumor cell lines [HT1080/DR4 (sarcoma) and HL60/ADR (leukemia)] and compared with the nonimmunosuppressive cyclosporine analogue PSC-833. In cell lines HT1080/DR4 (MRP/lung resistance-related protein phenotype) and HL60/ADR (MRP phenotype), doxorubicin resistance was significantly higher (250-fold and 180-fold, respectively) than that to paclitaxel (6-fold and 9-fold, respectively). With noncytotoxic concentrations of PAK-104P (1 and 5 microM), the reversal of doxorubicin resistance was significant but partial in HT1080/DR4 and HL60/ADR cells (dose-modifying factor for 5.0 microM PAK-104P, 25.0 and 31.2, respectively), whereas complete reversal of paclitaxel resistance was achieved in HL60/ADR cells. In contrast, PSC-833 modulation of doxorubicin and paclitaxel resistance was modest. Cellular drug uptake and retention studies by flow cytometry analysis demonstrated that PAK-104P was effective in restoring cellular doxorubicin concentrations in resistant cells to levels comparable to those obtained in parental cells. In athymic nude mice, PAK-104P significantly potentiated the therapeutic efficacy of doxorubicin and paclitaxel against resistant HT1080/DR4 xenografts. Of significance is that the maximum tolerated doses of doxorubicin and paclitaxel were administered in combination with PAK-104P, documenting improvement in the therapeutic index of these agents. In addition to reversing P-glycoprotein-mediated MDR, the pyridine analogue PAK-104P provides an example of an effective in vivo modulator of MRP-mediated MDR.
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PMID:PAK-104P, a pyridine analogue, reverses paclitaxel and doxorubicin resistance in cell lines and nude mice bearing xenografts that overexpress the multidrug resistance protein. 981 80

Overexpression of ATP-dependent drug efflux pumps, P-glycoprotein (Pgp) or multidrug resistance-associated protein (MRP), confers multidrug resistance to tumor cells. Modulators of multidrug resistance block the action of these pumps, thereby sensitizing cells to oncolytics. A potent Pgp modulator is LY335979, which fully sensitizes Pgp-expressing cells at 0.1 microM in cytotoxicity assays and for which Pgp has an affinity of 59 nM. The present study examines its effect on MRP1-mediated drug resistance and cytochrome P-450 (CYP) activity and its ability to serve as a Pgp substrate. Drug resistance was examined with HL60/ADR and MRP1-transfected HeLa-T5 cells. Drug cytotoxicity was unaffected by 1 microM LY335979; leukotriene C4 uptake into HeLa-T5 membrane vesicles was unaffected. Because the substrate specificity of Pgp and CYP3A overlap, the effect of LY335979 on the 1'-hydroxylation of midazolam by CYP3A in human liver microsomes was examined. The apparent K(i) was 3.8 microM, approximately 60-fold higher than the affinity of Pgp for LY335979. The modulator's effect on Pgp was evaluated with Pgp-overexpressing CEM/vinblastine (VLB)(100) and parental CCRF-CEM cells. Both cell lines accumulated [(3)H]LY335979 equally well and did not efflux [(3)H]LY335979 during a 3-h incubation, indicating that it is not a substrate of Pgp. Equilibrium-binding studies with CEM/VLB(100) plasma membranes and [(3)H]LY335979 showed that Pgp had a K(d) of 73 nM, which is in good agreement with the previously determined K(i) value. Thus, LY335979 is an extremely potent Pgp, and not MRP1 or MRP2, modulator and has a significantly lower affinity for CYP3A than for Pgp.
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PMID:Selectivity of the multidrug resistance modulator, LY335979, for P-glycoprotein and effect on cytochrome P-450 activities. 1041 2

P-glycoprotein (P-gp) is a membranous ATPase responsible for the multidrug resistance phenotype. The effect on P-gp-mediated transport of anthracyclines of cell irradiation in the presence of 2,2-diphenyl-5-[N-1-(o-azidophenyl)ethylamino]valeronitrile (VP*), a photoactivable analogue of verapamil was studied in viable K562/ADR cells. The derivatives were daunorubicin (DNR), idarubicin (IDA), 8-(S)-fluoro-idarubicin (F-IDA), 2'-bromo-4'-epidaunorubicin (Br-DNR) and pirarubicin (PIRA). It was observed that the irradiation in the presence of the verapamil analogue was unable to completely inhibit the P-gp-mediated efflux of anthracyclines and we estimated that P-gp retained 10-20% of its ability to pump these toxins. The ability of verapamil, DNR, IDA, F-IDA, Br-DNR and PIRA to inhibit the effect of VP* was studied. For this purpose, cells were irradiated in the presence of VP* and various concentrations of either verapamil or of one of the anthracyclines and then the P-gp functionality was checked by its ability to pump pirarubicin. It was observed that (i) the effect observed, when cells were irradiated in the presence of VP*, was completely blocked by the presence of verapamil; (ii) that anthracyclines are able to partially inhibit the VP* effect. This inhibition occurs at low concentration of anthracycline and depends on the nature of the derivative used. With those used in that study, after the photoirradiation of K562 ADR cells in the presence of VP* and anthracycline, P-gp has retained 50 +/- 5% of its functionality. The anthracycline concentration required for this inhibition is rather low, the total drug concentration yielding 50% of the effect ranged from 0.5 (Br-DNR) to 4 microM (F-IDA). The corresponding cytosolic concentrations are highly correlated with the values of Km determined previously.
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PMID:Partial inhibition of the P-glycoprotein-mediated transport of anthracyclines in viable resistant K562 cells after irradiation in the presence of a verapamil analogue. 1041 60

Graft-copolymers, containing poly(ethylene glycol) (PEG) and polyethyleneimine (PEI) chains have been proposed as carriers for delivery of phosphorothioate oligonucleotides (SODNs). Complexes of such copolymers with SODN self-assemble into particles having a core of neutralized PEI and SODN and a corona of PEG. Transferrin molecules are attached to the PEG corona using avidin/biotin construct. For this purpose, biotin moieties are covalently linked to the free ends of the PEG chains in the PEG-g-PEI copolymer. SODNs are reacted with mixtures of biotinylated and biotin-free PEG-g-PEI copolymers of various compositions to adjust the number of the biotin moieties in the complex. Resulting complexes have small size (ca. 40 nm) and do not aggregate in aqueous solutions for at least several days. To attach transferrin, they are supplemented first with avidin and then with biotin-transferrin conjugate. This increases the effective diameter of the particles to ca. 75-103 nm, depending on the composition of the complex. Cellular accumulation and fluorescence microscopy studies characterize the effects of these modifications on interaction of fluorescently labeled SODNs with KBv cell monolayers. The data suggest significant enhancement of SODN association with cells resulting from modification of the complex with transferrin. SODN complimentary to the site 546-565 of human mdr 1-mRNA was used to inhibit expression of the drug efflux transporter, P-glycoprotein (P-gp), in multiple drug resistant (MDR) cancer cells (KBv, MCF-7 ADR). Accumulation of a P-gp specific probe, rhodamine 123, in the cell monolayers is used to characterize the effects on P-gp efflux system following the treatment of the cells with antisense SODN or its complexes. This study suggests that antisense SODN incorporated in the complexes retain the ability to inhibit P-gp efflux system, while complexes of the randomized control SODN are inactive. Therefore, the antisense SODN is released from the complex and interacts with its intracellular target upon interaction of the complexes with the cells. Furthermore, modification of the complexes with transferrin leads to a significant increase of the effects of the antisense SODN on the P-gp efflux system in the cells. Overall, this study suggests that polyion complex micelles with protein-modified corona are promising tools for the delivery of antisense SODN.
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PMID:Polyion complex micelles with protein-modified corona for receptor-mediated delivery of oligonucleotides into cells. 1050 53

The effect of an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-Adriamycin-OV-TLl6 antibody conjugate [P(GFLG)-ADR-Ab] on OVCAR-3 human ovarian carcinoma cells was studied. A nontargeted HPMA copolymer-ADR conjugate (P(GFLG)-ADR) and free ADR were the controls. The IC(50) doses were 0.65, 3.0, and 65 microM for free ADR, targeted P(GFLG)-ADR-Ab conjugate, and nontargeted P(GFLG)-ADR conjugate, respectively. These differences reflect the different mechanisms of cell entry of the compounds evaluated. Free ADR and HPMA copolymer-ADR conjugates had different impacts on the expression of MDR1, MRP, c-fos, c-jun, and bcl-2 genes which encode the P-glycoprotein (MDR1) and the multidrug resistance-associated protein (MRP) efflux pumps, and play an important role in cell death signaling pathways (c-fos, c-jun, and bcl-2). Whereas high doses of free ADR induced MDR1 gene expression, HPMA copolymer-bound ADR appeared to be without effect. On the contrary, expression of the MRP gene was not influenced by free ADR, whereas HPMA copolymer-ADR conjugates seemed to suppress the gene expression in a concentration-dependent manner. There were differences in the expression of c-fos, c-jun, and bcl-2 genes after the incubation of OVCAR-3 cells with free and HPMA copolymer-bound ADR indicating differences in activation of cell death signaling pathways.
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PMID:HPMA copolymer-anticancer drug-OV-TL16 antibody conjugates. 3. The effect of free and polymer-bound adriamycin on the expression of some genes in the OVCAR-3 human ovarian carcinoma cell line. 1061 22

1. The combined effects of the macrolide antibiotics erythromycin, josamycin, clarithromycin and YM17K (3,4'-dideoxy mycaminosyl tylonolide hydrochloride) on in vitro intracellular accumulation of vinblastine or cyclosporine (Cs)A and on the in vivo antitumour activity of vinblastine were investigated using mouse leukaemia P388 cells (P388/S) and anticancer drug-resistant (P388/ADR) cells. These effects were compared with those of a calcium antagonist (verapamil) or immunosuppressants (FK506 and CsA). 2. All tested macrolide antibiotics increased the accumulation of both vinblastine and CsA in P388/ADR cells in a dose-dependent manner, but their potency was lower than that of verapamil, CsA or FK506. 3. When vinblastine (200 microg/kg) was administered intraperitoneally with each of the macrolide antibiotics (10 or 100 mg/kg) or with verapamil (25 mg/kg) once a day for 10 days in P388/ADR-bearing mice, combined effects of vinblastine with the macrolide antibiotics (erythromycin, clarithromycin and YM17K) or verapamil were observed. 4. The present study suggests that macrolide antibiotics may overcome anticancer drug resistance by inhibiting the binding of vinblastine or CsA to P-glycoprotein in P388/ADR cells. 5. We believe that these results are encouraging for combination chemotherapy to overcome P-glycoprotein-dependent anticancer drug-resistant tumours in clinical practice.
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PMID:Reversal of anticancer drug resistance by macrolide antibiotics in vitro and in vivo. 1090 87


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