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)

Modulation of the expression of P-glycoprotein, a plasma membrane protein associated with multidrug resistance, was examined in drug-sensitive and drug-resistant tumor cells treated with leukoregulin, a M(r) 50,000 cytokine from human lymphocytes that rapidly permeabilizes the plasma membrane of many tumor cells facilitating the uptake of doxorubicin and other tumor-inhibitory antibiotics. P-glycoprotein expression was measured flow cytometrically by the binding of C219 or MRK16 monoclonal antibody to multidrug-sensitive human K562 erythroleukemia and 8226/S myeloma cells, compared to multidrug-resistant 8226/DOX40 myeloma cells. Cells were treated for up to 2 h with up to 80 units of leukoregulin/ml or one of a variety of unrelated cytokines including interleukin 1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, colony-stimulating factor, macrophage colony-stimulating factor, granulocyte macrophage colony-stimulating factor, tumor necrosis factor alpha, gamma-interferon, alpha-interferon, epidermal growth factor, platelet-derived growth factor AA, platelet-derived growth factor BB, insulin-like growth factor I, insulin-like growth factor II, fibroblast growth factor, or transforming growth factor beta. Leukoregulin caused a concentration-dependent decrease in P-glycoprotein expression; however, P-glycoprotein expression was unaffected by the other cytokines (< 12% decrease in expression). Leukoregulin-induced membrane permeabilization, determined flow cytometrically by intracellular fluorescein efflux, and decreased P-glycoprotein expression occurred simultaneously within 15 min in drug-sensitive and -resistant cells. Enhanced doxorubicin uptake, measured flow cytometrically by doxorubicin influx, was also present within 15 min. Leukoregulin enhancement of doxorubicin uptake and increased membrane permeability varied directly with the decrease in P-glycoprotein expression. Leukoregulin in combination with doxorubicin enhanced the inhibition of cell proliferation in 8226/DOX40 multidrug-resistant cells over expressing P-glycoprotein. In contrast, combined treatment of HL-60/MX2 multidrug-resistant human promyelocytic leukemia cells that do not overexpress P-glycoprotein in association with their multidrug resistance resulted in no greater growth inhibition than observed with HL-60/MX2 cells treated with doxorubicin alone. This is the first demonstration that a naturally occurring macromolecule with anticancer activities can modulate the expression of P-glycoprotein concomitant with enhanced drug uptake and inhibition of cell proliferation.
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PMID:Decreased P-glycoprotein expression in multidrug-sensitive and -resistant human myeloma cells induced by the cytokine leukoregulin. 135 22

The induction of murine erythroleukemia cells (MELC; DS19/Sc9) to terminal differentiation by hexamethylenebisacetamide (HMBA) is characterized by a latent period of 10-12 hr before onset of commitment to terminal-cell division and increased transcription of globin genes. MELC variants, derived from this parental cell line, selected for resistance to vincristine (VC), can be induced to differentiate with little or no latent period. This study shows that accelerated HMBA-induced commitment is characteristic of MELC with a low level (2- to 5-fold) of VC resistance in four independently derived cell lines. Both resistance to VC and accelerated differentiation are stable phenotypes for at least 50 passages (approximately 5 months) in the absence of VC. Low-level VC-resistant MELC do not display increased levels of P-glycoprotein or mdr1, mdr2, and mdr3 mRNAs, nor do they exhibit cross-resistance to colchicine or doxorubicin. These cells do show (i) increased level of protein kinase C activity, (ii) reduced accumulation of [3H]VC, and (iii) restoration of VC sensitivity in the presence of verapamil. MELC selected for higher levels of VC resistance (approximately 500-fold) do express high levels of P-glycoprotein and the mdr3 gene. During HMBA-induced differentiation, DS19/Sc9 decrease [3H]VC accumulation, but P-glycoprotein content does not change. A VC-transport-associated protein, also critical for the process of induced differentiation, may be constitutively present in VC-resistant MELC, accounting for their enhanced sensitivity to inducer. This protein accumulates by exposure of VC-sensitive cells to HMBA, contributing to their differentiation and decreased level of VC accumulation.
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PMID:Characteristics of erythroleukemia cells selected for vincristine resistance that have accelerated inducer-mediated differentiation. 167 43

The K562/VCR cell line, exhibiting acquired multidrug resistance (MDR) with increased expression of a cell surface glycoprotein (P-glycoprotein), was isolated from human erythroleukemia K562 cells. Various compounds that induced erythroid differentiation of K562 cells were tested for their effects on growth and differentiation of these K562/VCR cells. Sodium butyrate, hemin, 1-beta-D-arabinofuranosylcytosine, and erythroid differentiation factor (EDF) induced erythroid differentiation of K562/VCR cells as well as K562 cells. The MDR of K562/VCR cells was partly overcome by treatment with EDF but not with the other inducers. Expression of P-glycoprotein by K562/VCR cells was measured by radioimmunoassay using MRK16 monoclonal antibody. Results showed that EDF caused down-regulation of P-glycoprotein in K562/VCR cells, whereas the other inducers did not cause its down-regulation. Thus, in addition to inducing erythroid differentiation, EDF enhanced the sensitivity of K562/VCR cells to multidrugs and suppressed expression of P-glycoprotein. These results suggest that differentiation inducers may be useful in chemotherapy of leukemic MDR cells.
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PMID:Inhibition by erythroid differentiation factor (activin A) of P-glycoprotein expression in multidrug-resistant human K562 erythroleukemia cells. 167 36

Hexamethylene bisacetamide (HMBA) is a potent inducer of differentiation of murine erythroleukemia cells (MELC). Commitment, the irreversible initiation of the program of terminal-cell differentiation, is first detected in HMBA-sensitive DS19-SC9 MELC in culture after 10 to 12 h of exposure to HMBA. Vincristine (VC)-resistant MELC derived from the DS19-SC9 MELC line display increased sensitivity to HMBA and become committed with little or no latent period. In the present study, we showed that the MELC line R1, which is resistant to HMBA-mediated differentiation, became sensitive to inducer if selected for a low level of VC resistance (less than 10 ng of VC per ml). Four independently derived VC-resistant cell lines from HMBA-resistant R1 cells, designated R1[VCR]a to R1[VCR]d, acquired sensitivity to HMBA and the accelerated kinetics of commitment that are characteristic of VC-resistant MELC derived from the parental DS19-SC9 cells. The calcium channel blocker verapamil suppresses the VC resistance of R1[VCR] cells but does not alter the accelerated response to HMBA. In R1[VCR] cells there was no detectable increase in the level of the 140-kilodalton P-glycoprotein. Transient inhibition of protein synthesis during the latent period delays inducer-mediated commitment of VC-sensitive DS19-SC9 MELC but does not alter the accelerated commitment kinetics of R1[VCR]a cells. Previously, we have reported evidence that protein kinase C beta (PKC beta) plays a role in HMBA-induced MELC differentiation and that compared with DS19-SC9 cells, R1 cells have a relatively low level and R1[VCR]a cells have a high level of PKC beta. These findings suggest that (i) acquisition of VC resistance overcomes the block acquired by R1 cells to HMBA-mediated differentiation; (ii) the accelerated kinetics of HMBA-induced commitment of VC-resistant MELC is not dependent on the verapamil-sensitive transport channel that is responsible, at least in part, for resistance to VC; (iii) in VC-resistant MELC, there is constitutive expression or accumulation of a protein required for HMBA-induced differentiation; and (iv) an elevated level of PKC beta activity may play a role in the altered response of R1[VCR] and other VC-resistant MELC to HMBA.
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PMID:Conversion of differentiation inducer resistance to differentiation inducer sensitivity in erythroleukemia cells. 197 44

First-step Adriamycin (doxorubicin)-resistant mutants of the murine erythroleukemia cell line PC4 were cloned from Adriamycin-containing (10 ng/ml) methylcellulose at a frequency of 3 x 10(-4). They demonstrated 1.6- to 2.4-fold stable resistance to Adriamycin. Most were cross-resistant to etoposide, but not to vincristine, and were without enhanced expression of mdr genes, which code for P-glycoproteins. Two different murine erythroleukemia cell lines, PC4 and C7D, were passaged in suspension culture into stepwise increasing amounts of Adriamycin. No high-level resistant mutants were isolated de novo; cells initially displayed low-level resistance to Adriamycin and etoposide. Two stepwise doublings of the drug concentration were needed before PC4 cells acquired vincristine resistance, but there was no detectable overexpression of mdr or a change in anthracycline uptake. In a subsequent doubling of Adriamycin concentration, the cells showed a further increase in resistance to all three drugs and now a decreased anthracycline accumulation. However, there was still no detectable increase in mdr expression as judged by Northern analysis of poly(A)+ enriched RNA and Western blot analysis of membrane proteins. Only after a fourth doubling of Adriamycin concentration did the cells demonstrate enhanced expression of mdr and P-glycoprotein. Equivalent mutants of C7D were selected, but generally at lower Adriamycin concentrations. Verapamil partially lowered resistance, but failed to restore parental susceptibility in any mutant; it caused an increased uptake in those mutants showing decreased anthracycline accumulation, including those that did not overexpress mdr. This study demonstrated different resistance phenotypes among mutants appearing spontaneously under stepwise drug selection; mutants with vincristine resistance and decreased anthracycline uptake preceded those associated with over-expression of P-glycoprotein.
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PMID:Sequential emergence of distinct resistance phenotypes in murine erythroleukemia cells under adriamycin selection: decreased anthracycline uptake precedes increased P-glycoprotein expression. 197 51

Human K562 erythroleukemia cells were selected in sequential steps for resistance to daunorubicin (K562/III) and found to be cross-resistant to a number of drugs, including vincristine, dactinomycin, doxorubicin, etoposide, and teniposide. In this paper, we report that the K562/III subline showed amplification of an mdr1 gene and its 4.5 kb transcript. Our results also show that non-ionic oligonucleoside methylphosphonates, complementary to the initiation codon and 15 bases upstream of the mdr1 gene, can completely inhibit the synthesis of P-glycoprotein and partially increase the toxicity of daunorubicin.
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PMID:Modulation of drug resistance in a daunorubicin resistant subline with oligonucleoside methylphosphonates. 257 74

The decrease of the intracellular concentration of drug in resistant cells compared to sensitive cells is, in most cases, correlated with the presence, in the membrane of resistant cells, of a 170-kDa P-glycoprotein responsible for an active efflux of the drug. In an attempt to identify mechanism(s) by which multidrug resistance can be circumvented, we have examined the cellular accumulation of 4'-O-tetrahydropyranyl-adriamycin, alone and in conjunction with various ionophores on the one hand and with cyclosporin A on the other hand. The present study was performed using a spectrofluorometric method with which it is possible to follow continuously the uptake and release of fluorescent molecules by living cells, as the incubation of the cells with the drug proceeds. Erythroleukemia K562 cell lines were used. Using experimental conditions in which these ionophores were unable to modify either the intracellular pH, or the transmembrane potential, or to induce an intracellular ATP depletion, we have shown that mobile ionophores as well as cyclosporin inhibit the P-glycoprotein-mediated efflux of 4'-O-tetrahydropyranyl-adriamycin in K562 resistant cells, whereas gramicidin, a channel-forming ionophore, does not. The concentration that must be used to inhibit 50% of the efflux was 0.7 microM for valinomycin, 0.4 microM for nonactin, 0.2 microM for nigericin, 1.1 microM for monensin, 0.4 microM for lasalocid, 1.2 microM for calcimycin and 0.4 microM for cyclosporin. Due to the high toxicity of the ionophores, the observation that they increased 4'-O-tetrahydropyranyl-adriamycin accumulation in the multidrug-resistant cells is not correlated with an effect of these compounds on drug resistance. However, the correlation exists in the case of cyclosporin. From our data showing that lipophilic neutral complexes, formed between carboxylic ionophores and metal ions, are both able to inhibit the P-glycoprotein-mediated efflux of anthracycline we can infer that the lipophilicity but not the cationic charge is an important physical property.
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PMID:Mobile ionophores are a novel class of P-glycoprotein inhibitors. The effects of ionophores on 4'-O-tetrahydropyranyl-adriamycin incorporation in K562 drug-resistant cells. 751 90

A multidrug-resistant (MDR) variant, K562/Dox, was selected from repeated exposure of human erythroleukemia cell line K562 to doxorubicin (Dox). K562/Dox displayed typical MDR features with respect to its cross-resistance to a variety of functionally and structurally unrelated compounds: vincristine (Vin), Dox, mitomycin C, reduced steady-state intracellular anthracycline accumulation, and elevated P-glycoprotein expression/mdr1 mRNA transcription/mdr1 gene amplification. Nevertheless, by incubation of cells with Dox/epirubicin (Epi)/daunorubicin (Dau) (5-80 micrograms/ml), the initial drug uptake was similar (p > 0.05) in K562/Dox and K562 cells, suggesting P-glycoprotein-mediated drug efflux would not occur unless a relatively high cellular drug concentration was reached. After 8 h incubation of cells with 50 ng/ml Dox (5 times higher than its IC50 to K562 cells), there were only slight differences (p > 0.05) in intracellular drug levels between K562/Dox and K562 cells, clearly indicating that K562/Dox, circumventing drug toxicity in this case, was irrelevant to reduced drug accumulation caused by P-glycoprotein. Similar results were obtained when Epi or Dau was applied. Despite complete restoration of anthracycline accumulation in K562/Dox cells in the presence of 6 mumol/l verapamil, the reversal of their drug resistance was incomplete. These results suggest that P-glycoprotein-mediated drug efflux possibly did not play a primary role in the drug resistance of K562/Dox cells.
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PMID:Does P-glycoprotein play a pivotal role in the drug resistance of an MDR variant, K562/Dox? 755 11

We studied the restoration of doxorubicin accumulation and sensitivity by verapamil and quinine in a variant of the human erythroleukemia cell line K562 selected for resistance to doxorubicin and presenting a multidrug-resistance (MDR) phenotype. Verapamil was able to completely restore doxorubicin accumulation in the resistant cells to the level obtained in sensitive cells, but only partially reversed doxorubicin resistance. Quinine, in contrast, had a relatively weak effect on doxorubicin accumulation but was able to completely restore doxorubicin sensitivity in the resistant cells. In addition, verapamil was able to decrease azidopine binding to P-glycoprotein, whereas quinine was not. Quinine also modified the intracellular tolerance to doxorubicin, which suggests that it is able to modify drug distribution within the cells. Confocal microscopy revealed that verapamil and quinine were able to restore nuclear fluorescence staining of doxorubicin in resistant cells; since this was obtained for quinine without significant increase of doxorubicin accumulation, this observation confirms that quinine acts principally on doxorubicin redistribution within the cells, allowing the drug to reach its nuclear targets. When used in association, verapamil and quinine reversed doxorubicin resistance in a synergistic fashion. We conclude that verapamil and quinine do not share the same targets for reversal of MDR in this cell line; whereas verapamil directly interferes with P-glycoprotein and mainly governs drug accumulation, quinine has essentially intracellular targets involved in drug redistribution from sequestration compartments.
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PMID:Differential effects of verapamil and quinine on the reversal of doxorubicin resistance in a human leukemia cell line. 762 69

The characteristics of volume-activated chloride currents, drug transport function and levels of P-glycoprotein (PgP) expression were compared between two human chronic erythroleukemia cell lines: a parental (K562) cell line and a derivative obtained by vinblastine selection (K562 VBL400). Parental K562 cells showed no detectable P-glycoprotein expression, measured at the protein level (immunofluorescence labeling with monoclonal antibodies), and had very low levels of MDR-1 mRNA expression (RT-PCR analysis), when compared with levels measured in K562 VBL400. Differences in Pgp-mediated transport were estimated by comparing the rates of Fluo3 accumulation. The higher drug-transport function of K562 VBL400 cells (e.g., lower Fluo3 accumulation) correlated with their elevated levels of MDR-1. The rate of dye transport was sensitive to verapamil but was not affected by the tonicity of the extracellular medium. In contrast to the clear differences in transport function, the characteristics of chloride currents induced by cell swelling were indistinguishable between the two cell lines. Currents measured in the whole-cell configuration were outwardly rectifying, had a higher permeability to iodide than to chloride (SCN- > I- > Cl- > gluconate), were potently blocked by NPPB and were unresponsive to verapamil. The percentage of responding cells and the mean current density were nearly identical in both cell lines. In addition, activation of the volume-sensitive current was not prevented during whole-cell recordings obtained with pipettes containing high concentration of cytotoxic drugs (vincristine or vinblastine). These results do not lend support to the previously reported association between Pgp expression and volume-sensitive chloride channels, and suggest that a different protein is responsible for this type of chloride channel in K562 cells.
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PMID:Drug-transport and volume-activated chloride channel functions in human erythroleukemia cells: relation to expression level of P-glycoprotein. 763 88


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