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

Multidrug resistance (MDR) is a phenomenon by which tumor cells exposed to a single anti-proliferative agent acquire resistance to other structurally and functionally unrelated drugs. The classical form of MDR is caused by a plasma-membrane protein currently named P-glycoprotein or P-170 encoded by the human mdr-1 gene in its functional isoform. In vitro cell lines expressing P-170 usually also present phenotypic and functional alterations. In the present study we report that the cytotoxicity mediated by tumor necrosis factor alpha (TNF alpha) in MDR variants of the human T-lymphoblastoid CEM cell line is associated with apoptosis (programmed cell death). Susceptibility of MDR cells to apoptosis was increased upon cycloheximide + TNF alpha sequential treatment, whereby the impairment of protein synthesis due to the former agent was followed by the effect of cytokine exposure. Massive apoptosis of P-170-positive cells, but not of controls, was also obtained by depletion of nutrients (i.e., serum starvation). In contrast, TNF-alpha exerted a similar apoptotic effect in epithelial (MCF-7) or myeloma (S8226) drug-sensitive/ -resistant cell pairs. However, the MDR variant of myeloma S8226 was more sensitive to the cytostatic effect of TNF alpha than the parental drug-sensitive cell line. These results suggest that the presence of the MDR phenotype may be associated with increased histotype-dependent cell susceptibility to specific, protein-synthesis-independent, apoptotic pathways.
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PMID:Tumor necrosis factor alpha is a powerful apoptotic inducer in lymphoid leukemic cells expressing the P-170 glycoprotein. 876 May 94

Multidrug resistance in hematologic malignancies and some solid tumors is mediated by a cell membrane pump known as the P-glycoprotein (P-gp). P-gp rapidly transports a variety of heterocyclic agents (including many natural product antiproliferative drugs) out of tumor cells thus abrogating their anticancer effects. P-gp can be competitively inhibited by exposure to antirheumatic drugs including antimalarials and cyclosporin A. Such inhibitors are being used as chemosensitizers (CS) to enhance the effects of chemotherapy in drug resistant tumors. P-gp is also expressed by some normal cells including macrophages and cytotoxic lymphocytes. Recent studies of purified natural killer (NK) cells have shown that both the drug efflux and NK cytotoxic functions can be inhibited by CS agents, suggesting that both drug efflux and cytotoxicity may be mediated by P-gp's molecular transport function. NK cell cytotoxicity is mediated by secreted molecules such as granzymes and perforins. Both tumor necrosis factor alpha (TNF-alpha) producing macrophages and NK cells are present in the synovial tissues and fluid in early and advanced rheumatoid arthritis (RA). We hypothesize that antiarthritic effects of the antimalarials and cyclosporine and perhaps glucocorticoids are partially attributable to the inhibition of P-gp function thereby blocking TNF-alpha release by macrophages, TNF-alpha activation of NK cells, and NK cell secretion of cytotoxins in the rheumatoid joint. This hypothesis permits the mechanism of action of some antirheumatic drugs to be classified, and may aid in the development of combination therapy for RA and other autoimmune disorders.
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PMID:Relevance of multidrug resistance to rheumatoid arthritis: development of a new therapeutic hypothesis. 883 64

Effects of xanthine derivatives (pentoxifylline, caffeine, theophylline, 1-methyl-3-isobutylxanthine) on P-glycoprotein mediated vincristine resistance of L1210/VCR mouse leukemic cell subline were studied. From the applied xanthines only PTX was found to reverse the vincristine resistance of the above cells. Moreover, only PTX, but not other xanthine, increased the accumulation of [3H]vincristine by L1210/VCR cells. Thus it may be concluded that PTX-induced reversal of vincristine resistance could not be explained from the point of known pharmacological effects of PTX that are common for other xanthines such as inhibition of phosphodiesterase activity, calcium mobilizing effect, inhibition of tumor necrosis factor alpha (TNF), etc.
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PMID:Overcoming of P-glycoprotein mediated vincristine resistance of L1210/VCR mouse leukemic cells could be induced by pentoxifyline but not by theophylline and caffeine. 884 53

Mammalian liver exhibits expression of members of the family of multidrug resistance (mdr) transporters (P-glycoproteins). P-glycoprotein isoforms encoded by mdr1 genes participate in extrusion of an array of xenobiotics into the bile. Induction of mdr1b mRNA expression has been shown to occur in rat hepatocytes in response to hepatotrophic growth factors. As the cytokine tumor necrosis factor alpha (TNF-alpha) is known to exert a direct mitogenic effect on hepatocytes, its influence on mdr1b expression was investigated. In primary rat hepatocytes cultured in the absence of TNF-alpha, a time-dependent increase in basal expression of mdr1b mRNA and in immunodetectable P-glycoprotein was observed. In cells treated with TNF-alpha (4,000 U/ml) for 3 days, expression of mdr1b mRNA and of immunodetectable P-glycoprotein was induced approximately twofold. Moreover, intracellular steady-state levels of the mdr1 substrate rhodamine 123 were decreased in cells pretreated with TNF-alpha in comparison to controls, indicating an increase in functional transporter(s) mediating dye extrusion. Treatment of hepatocytes with antioxidants (1 mM ascorbic acid and 2% dimethyl sulfoxide) for 3 days markedly suppressed mdr1b mRNA and P-glycoprotein expression both in cells cultured in the presence of TNF-alpha and in the absence of the cytokine, but did not fully abolish mdr1b mRNA induction by TNF-alpha, supporting the notion that reactive oxygen species participate in regulation of basal mdr1b gene expression during hepatocyte culture. In conclusion, the present data indicate that by inducing mdr1b expression in hepatocytes, TNF-alpha may affect the capacity of the liver for extrusion or detoxification of endogenous or xenobiotic mdr1 substrates.
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PMID:Induction of mdr1b mRNA and P-glycoprotein expression by tumor necrosis factor alpha in primary rat hepatocyte cultures. 969 3

The toxicity of fumonisin B(1) (FB(1)) was investigated in male mdr1a/1b double knockout (MDRK) mice, lacking the drug-transporting P-glycoproteins. These transgenic animals are deficient in their blood:brain barrier and accumulate different drugs in brain and other tissues. The MDRK and their wild-type counterparts, FVB mice, were injected subcutaneously with 2.25 mg/kg per day of FB(1) for 5 days and sampled one day after the last treatment in a protocol that has resulted in marked hepatic and renal damage in other strains. FB(1) caused liver enlargement in both FVB and MDRK. Hematological parameters were not affected in either strain. Plasma levels of alanine aminotransferase and aspartate aminotransferase, measures of liver damage, were increased by FB(1) in both FVB and MDRK mice. Histopathological evaluation of liver corroborated this finding. Kidney lesions were induced by FB(1) in both types of mice. Concentrations of free sphingosine and sphinganine increased in liver and kidney of both strains after the FB(1) treatment, although the increase in liver sphingoid bases was half as much in MDRK as compared to FVB. The levels of sphinganine-containing complex sphingolipids were increased in kidney. The levels of sphingosine-containing complex sphingolipids in kidney were unaffected by FB(1) treatment but were significantly lower in control MDRK than in FVB mice. The levels of neurotransmitters and their metabolites were similarly affected in both strains by FB(1), suggesting no influence of disrupted blood:brain barrier on FB(1)-induced neurotoxicity. In both strains, the liver mRNA for tumor necrosis factor alpha was increased; however, the increase was statistically significant only in FVB. It was apparent that mice deficient in P-glycoprotein do not exhibit greater sensitivity to FB(1), the cellular or brain transport of FB(1) appears to be independent of this multidrug transporting system.
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PMID:Fumonisin toxicity in a transgenic mouse model lacking the mdr1a/1b P-glycoprotein genes. 1092 70

The effects of Klebsiella pneumoniae endotoxin on the biliary excretion and renal handling of rhodamine-123 were investigated in rats at different times after intraperitoneal injection (1 mg/kg of body weight). The typical substrates for P glycoprotein, i.e., cyclosporine, colchicine, and erythromycin, inhibited the biliary clearance of rhodamine-123, whereas a substrate for organic cation transporter, cimetidine, did not inhibit clearance, suggesting that rhodamine-123 is transported mainly by P glycoprotein. The biliary, renal, and tubular secretory clearances of rhodamine-123 and the glomerular filtration rate significantly decreased 6 h after injection of endotoxin but returned to control levels by 24 h. These results suggest that endotoxin-induced decreases in P-glycoprotein-mediated biliary excretion and renal handling of rhodamine-123 were probably due to impairment of P-glycoprotein-mediated transport ability. Pretreatment with pentoxifylline (50 mg/kg) significantly inhibited endotoxin-induced increases in tumor necrosis factor alpha (TNF-alpha) levels in plasma, which ameliorated the endotoxin-induced reduction of the biliary excretion of rhodamine-123. It is likely that endotoxin-induced impairment of the transport of rhodamine-123 is caused, in part, by overproduction of TNF-alpha. The effect of endotoxin on the expression of P-glycoprotein mRNA in liver and kidneys of rats was investigated by using a reverse transcriptase PCR. The expression of Mdr1a mRNA in both liver and kidney decreased 6 h after endotoxin injection and returned to control levels after 24 h, whereas the expression of Mdr1b mRNA in liver increased at both times and that in kidney decreased at 24 h. These findings suggest that K. pneumoniae endotoxin dramatically decreases P-glycoprotein-mediated biliary and renal excretion of rhodamine-123 probably by decreasing the expression of Mdr1a, which is likely due to increased plasma TNF-alpha levels.
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PMID:Effect of endotoxin on P-glycoprotein-mediated biliary and renal excretion of rhodamine-123 in rats. 1170 25

The effect of Shiga-like toxin II (SLT-II) (2 microg/animal), which was derived from Escherichia coli O157:H7, on renal handling of levofloxacin (LVX), a model drug for quinolone antimicrobial agents, was investigated in rats 24 h after intravenous injection. In histopathological examination, acute tubular injury was observed in SLT-II-treated rats, but the glomeruli were not injured. SLT-II significantly increased the steady-state concentration of LVX in plasma to 1.5-fold that of control rats. SLT-II induced significant decreases in the glomerular filtration rate (GFR) and renal clearance (CL(R)) of LVX. SLT-II slightly, but significantly, increased the unbound fraction and decreased renal plasma flow with no change in the extraction ratio of p-aminohippurate. SLT-II significantly increased concentrations of tumor necrosis factor alpha (TNF-alpha) and nitrite and nitrate (NOx) in plasma. The TNF-alpha inhibitor pentoxifylline partly, but significantly, inhibited SLT-II-induced decreases in the GFR and CL(R) of LVX; in contrast, S-methylisothiourea, a selective inhibitor of inducible nitric oxide synthase, did not. Western blotting analysis revealed that SLT-II did not alter the levels of multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein in kidneys 24 h after injection, assuming the lack of involvement of Mrp2 and P-glycoprotein in SLT-II-induced acute renal tubular injury and renal handling of LVX observed 24 h after SLT-II injection. The present study suggests that SLT-II impairs the renal handling of LVX by decreasing GFR and causing decreased renal plasma flow.
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PMID:Shiga-like toxin II derived from Escherichia coli O157:H7 modifies renal handling of levofloxacin in rats. 1195 91

The occurrence of the multidrug resistance phenotype still represents a limiting factor for successful cancer chemotherapy. Numerous efforts have been made to develop strategies for reversal and/or modulation of this major therapy obstacle through targeting at different levels of intervention. The phenomenon of MDR is often associated with overexpression of resistance-associated genes. Since the classical type of MDR in human cancers is mainly mediated by the P-glycoprotein encoded by the multidrug resistance gene 1, mdr1, the majority of reversal approaches target the expression and/or function of the mdr1 gene/P-glycoprotein. Due to the fact that the multidrug phenotype always represents the net effect of a panel of resistance-associated genes/gene products, other resistance genes, e.g. those encoding the multidrug resistance-associated protein MRP or the lung resistance protein LRP, were included in the studies. Cytokines such as tumor necrosis factor alpha and interleukin-2 have been shown to modulate the MDR phenotype in different experimental settings in vitro and in vivo. Several studies have been performed to evaluate their potential as chemosensitizers of tumor cells in the context of a combined application of MDR-associated anticancer drugs like doxorubicin and vincristine with cytokines. Moreover, the capability of cytokines to modulate the expression of MDR-associated genes was demonstrated, either by external addition or by transduction of the respective cytokine gene. Knowledge of the combination effects of cytokines and cytostatics and its link to their MDR-modulating capacity may contribute to a more efficient and to a more individualized immuno-chemotherapy of human malignancies.
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PMID:Cytokine-mediated reversal of multidrug resistance. 1900 98

Pharmacotherapy of brain HIV-1 infection may be limited by ABC transporters [i.e., P-glycoprotein (P-gp), multidrug resistance protein 1 (Mrp1)] that export antiretroviral drugs from HIV-1 brain cellular targets (i.e., astrocytes, microglia). Using an in vitro astrocyte model of an HIV-1 associated inflammatory response, our laboratory has shown that cytokines [i.e., tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1 beta, IL-6], which are secreted in response to HIV-1 envelope glycoprotein gp120 exposure, can decrease P-gp functional expression; however, it is unknown whether these same cytokines can alter expression and/or activity of other ABC transporters (i.e., Mrp1). In primary cultures of rat astrocytes, Mrp1 expression was increased by TNF-alpha (2.7-fold) but was not altered by IL-1 beta or IL-6. Cellular retention of 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, an Mrp substrate, was reduced in TNF-alpha-treated astrocytes, suggesting increased Mrp-mediated transport. Pharmacologic inhibition of nuclear factor-kappaB (NF-kappaB) signaling with SN50 prevented both TNF-alpha release and Mrp1 expression changes in astrocytes triggered with gp120; however, SN50 did not attenuate Mrp1 expression in cells triggered with TNF-alpha. In contrast, Mrp1 functional expression was not altered in the presence of gp120 or TNF-alpha when astrocyte cultures were pretreated with 1,9-pyrazoloanthrone (SP600125), an established c-Jun N-terminal kinase (JNK) inhibitor. SP600125 did not affect TNF-alpha release from cultured astrocytes triggered with gp120. Mrp1 mRNA expression was increased after treatment with gp120 (1.6-fold) or TNF-alpha (1.7-fold), suggesting altered Mrp1 gene transcription. These data suggest that gp120 and TNF-alpha can up-regulate Mrp1 expression in cultured astrocytes. Furthermore, our results imply that both NF-kappaB and JNK signaling are involved in Mrp1 regulation during an HIV-1 associated inflammatory response.
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PMID:Regulation of multidrug resistance protein 1 by tumor necrosis factor alpha in cultured glial cells: involvement of nuclear factor-kappaB and c-Jun N-terminal kinase signaling pathways. 2005 32


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