Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since March 1996, 93 consecutive samples of 45 adults and 41 children, suffering from acute leukemia, were evaluated prospectively for P-glycoprotein (P-gp) expression and function by flow cytometry. P-gp antigen expression was determined with the monoclonal antibodies 4E3 and MRK16. Transport function was assessed by measuring the modulating effect of verapamil on the intracellular retention of Rhodamine 123. P-gp positivity at relapse was not significantly more frequently than at initial diagnosis in our study group, neither with the immunologic assay, nor with the functional test. There was no correlation between the results of the immunologic and the functional test. Discordant test results were observed in 11/41 children (12/44 samples) and 14/45 adults (15/49 samples), independent of the type of leukemia. 2/12 and 2/15 samples scored positive with one of the monoclonal antibodies and were functionally inactive. In 10/12 and 13/15 samples however, an efflux pump was active and dependent of verapamil, but without detectable antigen. The functional flow cytometric assay allows evaluation of non-P-gp efflux pumps and, therefore, is more clinically relevant since it may better identify patients who would benefit from the use of P-gp inhibitors.
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PMID:Discordance of P-glycoprotein expression and function in acute leukemia. 1050 Jul 86

The development and spread of multidrug-resistant Plasmodium falciparum are major health concerns. The molecular mechanisms of multidrug resistance, including resistance to many quinoline-based antimalarials, are largely unknown. In this study, we report on the isolation and partial characterization of actinomycin D (actD)-resistant P. falciparum (3D7(R)/actD2.3) from a chloroquine-susceptible strain, 3D7. The stepwise selection of an actD-resistant clone (3D7(R)/actD2.3) led to the isolation and cloning of P. falciparum that grew in the presence of 2 ng/mL of actD. The parental isolate (3D7) did not grow in the presence of a 10-fold lower drug concentration (0.2 ng/mL). The latter estimate of parasite growth was determined by direct counting of parasites in infected red blood cells. Estimates of drug resistance levels to actD, using a [(3)H]hypoxanthine uptake and incorporation method, showed a 3-fold difference in the IC(50) between 3D7 and 3D7(R)/actD2.3. Interestingly, 3D7(R)/actD2.3 P. falciparum parasites were less sensitive to several antimalarials (chloroquine, mefloquine, quinidine, and artemisinin) and to the mitochondrial specific dye Rhodamine 123. Drug transport studies using [(3)H]actD showed that 3D7(R)/actD2.3 accumulated less drug than 3D7. Moreover, the accumulation of [(3)H]actD was energy dependent. To determine if Pfmdr1 expression, previously implicated in drug resistance to certain antimalarials, mediated the resistance phenotype of 3D7(R)/actD2.3, Pfmdr1 levels in 3D7 and 3D7(R)/actD2.3 were compared by Southern and northern blot analyses. Our results revealed no differences in Pfmdr1 copy number or mRNA levels between 3D7 and 3D7(R)/actD2.3. Furthermore, comparison of Pfmdr1 sequences between 3D7 and 3D7(R)/actD2.3 showed no differences. In addition, verapamil, which reverses P-glycoprotein-mediated drug resistance in mammalian cells, did not reverse the resistance of 3D7(R)/actD2.3 to actD or chloroquine. Taken together, the findings of this study demonstrated that in vitro selection of P. falciparum for resistance to actD leads to decreased sensitivity to diverse drugs and that this pleiotropic drug resistance is associated with reduced drug accumulation not mediated by Pfmdr1.
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PMID:Pleiotropic resistance to diverse antimalarials in actinomycin D-resistant Plasmodium falciparum. 1070 42

Human lung adenocarcinoma A549 cells sensitive and A549/DDP cells resistant to Cis-dichlorodiammine platinum[II] (cisplatin) exhibit different intracellular free calcium and calcium fluorescence images labeled with Fura-2/AM and Fluo-3/AM as judged by dual-excitation fluorescence assay, Miracal Imaging and Laser Scanning Confocal Microscopy (LSCM) of single cells. The concentration of intracellular free calcium of the resistant A549/ DDP cells is one third that of the sensitive A549 cells. The efflux of Rhodamine 123 in resistant A549/DDP cells is faster than that in sensitive A549 cells. In addition, A549/DDP cells have an increase of Phosphatidylinositol 4-kinase (PtdIns 4-kinase) activity in the plasma membrane. So it is tentatively suggested that the increase in PtIns 4-kinase activity resulting from lower intracellular Ca2+ concentration leads to an increase of its enzymatic products--PIP and PIP2, which may stimulate the activity of P-glycoprotein.
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PMID:Intracellular free calcium concentration and cisplatin resistance in human lung adenocarcinoma A549 cells. 1109 13

Taxanes antitumour agents such as paclitaxel and docetaxel represent a successful family of chemotherapeutic drugs. Unfortunately, acquired and innate resistance represents a clinical problem for these drugs. We investigated, on a panel of 7 human cancer cell lines, the growth inhibition effect of 3 newly developed taxanes (SB-T-1213, SB-T-1250 and SB-T-101187) with modification at the C10 and C3' positions of the taxane framework. These positions have been previously characterized as critical to make taxanes highly active against cells overexpressing the efflux pump P-glycoprotein (P-gp). Paclitaxel and docetaxel were used as reference compounds. Results unambiguously indicate the exceptional activity of the novel taxanes toward P-gp positive cells (up to >400 fold higher potency than that of paclitaxel). SB-T-1213 and SB-T-1250 are also substantially more active than the reference compounds against P-gp negative cells. To better understand the mechanisms underlying the enhanced activity of the newly developed taxanes, we performed cell cycle and apoptosis analysis. This study demonstrates that the striking growth inhibition effect exhibited by the novel taxanes is ascribed to their increased ability in inducing apoptosis and G(2)/M cell cycle block. SB-T-1213 and SB-T-1250 are also more active than reference compounds in inducing intracellular accumulation of the beta-tubulin subunits. Finally, it is revealed that these novel taxanes have ability to inhibit the function of the P-gp efflux pump on the basis of the Rhodamine 123 assay. These findings strongly suggest that SB-T-1213, SB-T-1250 and SB-T-101187 represent a new tool to overcome innate or acquired P-gp mediated taxane-resistance.
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PMID:Antitumour activity of novel taxanes that act at the same time as cytotoxic agents and P-glycoprotein inhibitors. 1110 78

A representative cause of multidrug resistance (MDR) is expression of the MDR gene (mdr1) and its product P-glycoprotein (P-gp). The function of P-gp is thought to be the extrusion of anticancer drugs from the cell against a concentration gradient. In acute myelogenous leukemia (AML), P-gp expression in leukemic blast cells at initial presentation has been reported to be 20% to 40%. The remission rate of acute leukemia patients is significantly lower in P-gp+ patients than in P-gp- patients. A significantly shorter survival and relapse-free survival in P-gp+ AML patients compared with P-gp- patients has been reported. Intracellular daunorubicin/Rhodamine123 content in P-gp+ leukemic blast cells is significantly lower than in P-gp- leukemic blast cells. By using a leukemic blast colony assay, lowered sensitivity to the anticancer drug was revealed not only in leukemic blast cells but also in leukemic progenitors. One method to overcome MDR with a possibility of clinical application is to use drugs that interfere with the function of P-gp. The addition of MS-209 in vitro as an MDR-reversing agent significantly enhanced the intracellular daunorubicin/Rhodamine 123 accumulation and the retention of P-gp+ leukemic blast cells to a level similar to that of P-gp- blast cells. Recent clinical trials using MDR-reversing agents have demonstrated some encouraging results in P-gp+ patients but not in P-gp- patients.
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PMID:Multidrug resistance of acute leukemia and a strategy to overcome it. 1119 7

The expression of P-glycoprotein (P-gp), encoded by the MDR1 gene, is an independent adverse prognostic factor for response and survival in de novo acute myeloid leukemia (AML). Little is known about MDR1 expression during the development of disease. The present study investigated whether MDR1 gene- related clonal selection occurs in the development from diagnosis to relapsed AML, using a genetic polymorphism of the MDR1 gene at position 2677. Expression and function of P-gp were studied using monoclonal antibodies MRK16 and UIC2 and the Rhodamine 123 retention assay with or without PSC 833. No difference was found in the levels of P-gp function and expression between diagnosis and relapse in purified paired blast samples from 30 patients with AML. Thirteen patients were homozygous for the genetic polymorphism of MDR1 (n = 7 for guanine, n = 6 for thymidine), whereas 17 patients were heterozygous (GT). In the heterozygous patients, no selective loss of one allele was observed at relapse. Homozygosity for the MDR1 gene (GG or TT) was associated with shorter relapse-free intervals (P =.002) and poor survival rates (P =.02), compared with heterozygous patients. No difference was found in P-gp expression or function in patients with AML with either of the allelic variants of the MDR1 gene. It was concluded that P-gp function or expression is not upregulated at relapse/refractory disease and expression of one of the allelic variants is not associated with altered P-gp expression or function in AML, consistent with the fact that MDR1 gene-related clonal selection does not occur when AML evolves to recurrent disease. (Blood. 2001;97:3605-3611)
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PMID:MDR1 gene-related clonal selection and P-glycoprotein function and expression in relapsed or refractory acute myeloid leukemia. 1136 57

P-glycoprotein (PGP) is an efflux pump physiologically expressed in the apical membrane of the proximal tubular cells. PGP may play a role in the elimination of exogenous substances such as chemotherapeutic drugs, calcium channel blockers and immunosuppressors. The involvement of renal PGP in the transport of endogenous substrates is under investigation. HK-2 is an immortalized proximal tubule cell line from normal adult human kidney, reported to retain a phenotype indicative of a well-differentiated state. No data regarding expression and/or activity of PGP in this cell line are available. The aim of this study was to ascertain the usefulness of HK-2 cell line to investigate the properties and roles of PGP in proximal tubular cells. PGP expression in HK-2 cells was determined by immunoblotting analysis using the monoclonal antibody C219. The activity of PGP was assessed by measuring the transport of the fluorescent probe Rhodamine 123 (R-123) in intact cell monostrates. The interactions of putative PGP modulators, including verapamil and cyclosporin A were also evaluated. Western blot revealed a C219 immunoreactive band of about 150 kDa consistent with the presence of PGP. HK-2 cells preloaded with R-123 rapidly effluxed the dye, the efflux being inhibited by verapamil. Verapamil and, to a major extent cyclosporin A, significantly increased R-123 intracellular accumulation. PGP immunoblottable amount was increased when cells were cultured in the presence of either cyclosporin A or dexamethasone. The results suggest that the HK-2 cells, among the various differentiation features of proximal tubules, retain also the expression of a functional PGP in their membranes and that both PGP activity and expression may be modulated by drugs. Therefore, HK-2 line appears a suitable and promising tool for the study in vitro of renal transport processes dependent on PGP.
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PMID:P-glycoprotein in HK-2 proximal tubule cell line. 1149 49

P-glycoproteins (P-gps) encoded by mdr1 (multidrug resistance) genes mediate extrusion of numerous lipophilic xeno- and endobiotics through the plasma membrane. Rhodamine 123 (Rh123), a fluorescent dye which is accumulated by mitochondria, is a mdr1 substrate and a well-established tool to study mdr1 transport activity. Inhibitors of mdr1-dependent transport such as verapamil or cyclosporin A have been found to decrease Rh123 efflux from mdr1-expressing cells. Mdr1b gene expression increases with time in primary rat hepatocyte culture. In hepatocytes cultured for 4 days and expressing high levels of P-gp, intracellular Rh123 accumulation was enhanced in the presence of mdr1 inhibitors (cyclosporin A, 8 and 80 microM, verapamil, 8 and 80 microM, or triton X-100, 8 microM). Surprisingly, in hepatocytes expressing low levels of P-gp (after 1 day of culture), time-dependent Rh123 accumulation was not enhanced, but delayed by cyclosporin A, verapamil or triton X-100. In these cells orthovanadate (50 microM), an inhibitor of P-glycoprotein ATPase activity, suppressed Rh123 accumulation, while tetraethylammonium (200 microM), an organic cation transporter (OCT) substrate, had no effect. The paradoxical delay in Rh123 accumulation by verapamil and cyclosporin A occurred eventhough these compounds decreased dye extrusion from Rh123 pre-loaded cells. These observations suggest that a hitherto unknown mechanism which is sensitive to modulators of mdr1-activity contributes to Rh123 uptake or accumulation in primary rat hepatocytes.
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PMID:Inhibitors of mdr1-dependent transport activity delay accumulation of the mdr1 substrate rhodamine 123 in primary rat hepatocyte cultures. 1155 29

Inhibition of tumor growth induced by treatment with direct current (DC) has been reported in several systems. In the current work, the cellular effects generated by the DC treatment of the human leukemic K562 cell line and its vincristine-resistant derivative K562-Lucena 1 were analyzed by trypan blue staining and transmission electron microscopy. DC stimulation induced cell lysis, alterations in shape, membrane extraction or discontinuity, and intense vacuolization of some cells. In addition, treatment of K562 and K562-Lucena 1 cells caused a marked decrease in viability. Since multidrug resistance is a major factor contributing with failure of chemotherapy in many tumors, the expression and function of P-glycoprotein (P-gp) in K562-Lucena 1 cells were also studied. The expression of mdr1, the gene encoding P-gp, was analyzed by reverse transcription polymerase chain reaction, which showed that this gene was equally expressed in either treated or untreated cells. These results were confirmed by flow cytometry with a monoclonal anti P-gp antibody and the Rhodamine 123 extrusion method, which revealed that P-gp surface expression and function were unaltered after DC treatment. Our results suggest that DC treatment does not affect P-gp in human leukemic cells, but affects their viability by mechanisms that would involve clear cellular effects, but also additional targets, whose relevance in dc treated tumoral cells is currently discussed.
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PMID:Direct current decreases cell viability but not P-glycoprotein expression and function in human multidrug resistant leukemic cells. 1156 32

Multidrug resistance due to overexpression of P-glycoprotein (Pgp) leads to reduced intracellular drug accumulation and makes the cells resistant to chemotherapy. In this study we focused on how drugs used in the supportive care of acute myeloid leukemia (AML) patients interfere with Pgp. The effect on intracellular accumulation of the fluorescent dye Rhodamine 123 (Rh 123) was studied in the human promyelocytic leukemia cell line HL-60 and two anthracycline resistant, Pgp expressing, sublines. Each drug was used at two different concentrations: plasma peak concentration and half the plasma peak concentration. Drugs which increased the Rh 123 uptake by > 10% were included in the second part of the study where the cytotoxic effect was tested in combination with daunorubicin. In the Rhodamine assay none of the tested drugs had any significant effect on the Rh 123 efflux in the resistant cell lines. Amphotericin B, cefuroxime, erythromycin and dixyrazin had minor effects on Rh 123 uptake but showed a significant additive effect to the toxicity of daunorubicin suggesting other mechanisms of action than reversal of Pgp. In conclusion this in vitro model where Rh 123 uptake was studied in an anthracycline resistant leukemia cell line could not demonstrate any significant interactions with Pgp for the tested drugs.
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PMID:Interactions between P-glycoprotein and drugs used in the supportive care of acute myeloid leukemia patients. 1169 5


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