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)

Sulphoraphane (SF), a naturally occurring isothiocyanate, is a potent anticarcinogen in animal experiments. The mechanism of action of sulphoraphane includes induction of Phase 2 detoxification enzymes, inhibition of carcinogen-activating Phase 1 enzymes, induction of apoptosis and cell cycle arrest, and anti-inflammation. We have recently found that it was accumulated in mammalian cells by up to several hundred-fold over the extracellular concentration, primarily by conjugation with intracellular GSH. The intracellular accumulation levels of SF can reach millimolar concentrations. The anticarcinogenic activity of SF is at least partly dependent on its accumulation levels in cells. Here we show, however, that the accumulated SF was rapidly exported mainly in the form of GSH conjugate (GS-SF) in cultured human cells. It appeared that to sustain the intracellular accumulation levels required a continuous uptake of SF to offset the rapid export of SF/GS-SF. These findings may have important implications for the development of an effective dosing regimen for SF. Moreover, the export was temperature-sensitive and was inhibited by known inhibitors of membrane pumps, suggesting the involvement of such a pump in exporting accumulated SF/GS-SF. Indeed, studies with human leukemia cells (HL60) with or without overexpression of multidrug resistance associated protein-1(MRP-1) and human myeloma cells (8226) with or without overexpression of P-glycoprotein-1 (Pgp-1) indicated that both MRP-1 and Pgp-1 are involved in the export of intracellular SF/GS-SF.
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PMID:High cellular accumulation of sulphoraphane, a dietary anticarcinogen, is followed by rapid transporter-mediated export as a glutathione conjugate. 1198 4

Transport of xenobiotics and their metabolites by ATP-binding cassette (ABC) transporters particularly P-glycoprotein (Pgp) and the multidrug resistance associated protein (MRP1) has been extensively studied during last decade. Our recent studies demonstrate that RLIP76, a previously known GTPase-activating protein catalyzes ATP-dependent, uphill transport of anionic glutathione conjugates as well as of weakly cationic anthracyclines including doxorubicin (Adriamycin), a widely used drug in cancer chemotherapy. RLIP76 has inherent ATPase activity, which is stimulated by doxorubicin and glutathione conjugates. RLIP76 does not meet the criteria for classical ABC proteins such as MRP1 or Pgp, but similar to ABC proteins, it has two ATP-binding sequences, (69)GKKKGK(74) and (418)GGIKDLSK(425). Mutations in these sequences abrogate its ATP-binding, ATPase activity, and transport function. Purified RLIP76 when reconstituted in proteoliposomes mediates ATP-dependent saturable transport of doxorubicin and glutathione conjugates. Transfection of K562 cells with RLIP76 confers these cells resistance to doxorubicin and 4-hydroxynonenal. Cells enriched with RLIP76 also acquire resistance to radiation toxicity. RLIP76 also catalyzes the transport of physiologic ligands such as leukotrienes (LTC4) and the conjugate of 4-hydroxynonenal and glutathione. In some cells (e.g., erythrocytes and lung cancer cells), the majority of transport activity for Adriamycin and glutathione conjugates including LTC4 is accounted for by RLIP76. These studies strongly suggest that RLIP76-mediated transport of organic ions has physiological and toxicological relevance and that it may play an important role in the mechanism of drug resistance.
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PMID:RLIP76, a novel transporter catalyzing ATP-dependent efflux of xenobiotics. 1243 96

Our study examines the ability of LY335979 (Zosuquidar trihydrochloride) to modulate 3 distinct ABC transporters that are mechanisms of drug resistance: P-glycoprotein (Pgp, ABCB1), multidrug resistance associated protein (MRP1, ABCC2) and breast cancer resistance protein (BCRP, ABCG2). Pgp-mediated resistance can be modulated by coadministration with the highly potent, selective inhibitor, LY335979. Modulation of resistance by mitoxantrone and vinorelbine, 2 drugs used to treat certain solid tumors, was examined in a 3-day cytotoxicity assay using a panel of HL60 leukemia cell lines or MCF-7 breast cancer transfectants. LY335979, at 0.5 microM, substantially reversed mitoxantrone resistance and fully reversed vinorelbine resistance of Pgp-expressing HL60/Vinc cells. However, LY335979 did not modulate drug resistance in the MRP1-expressing HL60/ADR or drug-sensitive parental HL60 cells. To ascertain if LY335979 modulates BCRP-mediated drug resistance, the sensitivity of 26-fold mitoxantrone resistant, BCRP-transfected MCF-7 cells was evaluated. Addition of 5 microM LY335979, a concentration approximately 100-fold higher than the affinity of Pgp, had little to no effect on the BCRP transfectant. [(125)I]Iodomycin photolabeled Pgp in CEM/VLB(100) membranes and was inhibited by 5 microM LY335979 and GF120918. No photolabeling of MRP or BCRP occurred in H69AR or MCF-7/BCRP membranes, respectively. These results further demonstrate that LY335979 is highly specific for Pgp and does not modulate MRP1- or BCRP-mediated resistance and can be used in combination with mitoxantrone and vinorelbine in tumor cells.
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PMID:Modulation of P-glycoprotein but not MRP1- or BCRP-mediated drug resistance by LY335979. 1245 64

The objective of this study was to determine the role of transport proteins in daunorubicin (Dnr) accumulation and efflux in leukemia cells from 36 patients with acute myeloid leukemia (AML). Mononuclear cells were isolated and incubated with 1 microM Dnr with/without addition of 3 microM cyclosporin A (CyA) or metabolic inhibitors (MI). Cellular Dnr concentration in leukemia blast cells was measured with flow cytometry. After washing and reincubation of the cells in drug-free medium, Dnr efflux was followed with/without addition of CyA or MI. Levels of mRNA expression for mdr1, multidrug resistance associated protein (mrp) and lung resistance protein (lrp) were determined with reverse transcriptase-polymerase chain reaction (RT-PCR). MI enhanced cellular Dnr accumulation to a higher extent than CyA whereas CyA reduced Dnr efflux more efficiently than MI (P<0.001). There was a significant difference in Dnr accumulation between samples with low and high mdr1 mRNA levels but only in the presence of MI or CyA. Our results imply that other factors than P-glycoprotein (Pgp) are of major importance for in vitro Dnr accumulation in AML blasts and that the role of Pgp as a drug efflux pump is not conclusive.
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PMID:Different effects of metabolic inhibitors and cyclosporin A on daunorubicin transport in leukemia cells from patients with AML. 1252 24

RLIP76 functions as an ATP-dependent transporter of amphiphilic chemotherapeutic drugs such as doxorubicin (DOX, adriamycin), as well as of glutathione-conjugates of endogenous electrophilic toxins such as 4-hydroxynonenal (4HNE). RLIP76 couples transport and ATP-hydrolysis with a 1:1 stoichiometry, making the ATPase activity of RLIP76 an excellent surrogate for its transport activity. Present studies were performed to determine the relationship of the RLIP76 ATPase activity with DOX and 4HNE resistance in a panel of 13 native human lung cancer cell lines. RLIP76 was purified from each cell line and homogeneity demonstrated by SDS-PAGE and amino acid composition analysis. Anti-RLIP76 antibodies were shown by Ouchterlony double immunodiffusion tests to be non-cross-reactive with any other proteins including P-glycoprotein (Pgp) or multidrug resistance associated protein (MRP). These antibodies completely immunoprecipitated ATPase activity of purified RLIP76 fractions, further confirming homogeneity of purified RLIP76. RLIP76 ATPase purified from NSCLC cell lines was about 2-fold more active than that from SCLC in the absence of the stimulator dinitrophenyl S-glutathione (206+/-47, n=7 vs. 94+/-22, n=6, nmol/min/mg protein, respectively), or in its presence (340+/-60, n=7 vs. 186+/-32, n=6, nmol/min/mg; p<0.01). Partial tryptic digest revealed a 44 kDa internal fragment of RLIP76 beginning at Thr-294 in NSCLC cell lines. This fragment was absent from all SCLC, suggesting the possibility that the activity of RLIP76 in SCLC and NSCLC is differentially regulated through post-translational modifications. Taken together, these findings suggest that RLIP76 activity is a general determinant of 4HNE and DOX resistance, and that its activity contributes to the drug-resistant phenotype of NSCLC.
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PMID:Role of RLIP76 in lung cancer doxorubicin resistance: I. The ATPase activity of RLIP76 correlates with doxorubicin and 4-hydroxynonenal resistance in lung cancer cells. 1252 36

Germ cell testicular cancers are well-curable neoplasms, because total remission can be achieved in about 80% of the cases. However, 15-20% of the patients die due to drug resistance (DR). A number of mechanisms of the multidrug resistance phenotype are known, including MDR/P-glycoprotein (P-gp) and the so-called multidrug resistance associated protein (MRP). Lung Resistance Protein (LRP) is an ATP dependent membrane transporter protein associated with MDR. In our present work we studied the expression of LRP in testicular cancers. LRP expression was determined by immunohistochemistry (IH), Western blot (WB) and RT-PCR techniques. Clinical resistance was defined in accordance with the clinical oncologic rules. In 29 (41%) of 70 primary testicular tumours and in 22 (63%) of 35 cases, elevated LRP levels were established by IH and WB, respectively. In the latter 63%, the LRP mRNA levels were elevated as well. Six cases of the 15 seminomas and 23 cases of the nonseminomatous germ cell tumours (NSGCT) proved to be positive. No relationship was demonstrated between LRP expression and the stage of the disease. Despite the LRP positivity of 6 tumour samples, all of the seminomas proved sensitive. Of the 39 sensitive NSGCT, 27 cases were LRP-negative, whereas 11 tumour samples of 16 patients belonging to the resistant group proved LRP-positive (p=0.04). The authors concluded that the expression of LRP is responsible for clinical drug resistance in non-seminomatous testicular cancer patients.
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PMID:[Lung resistance protein analysis in testicular cancer]. 1256 57

The ATP-binding cassette (ABC) transporter superfamily is a large gene family that has been highly conserved throughout evolution. The physiological importance of these membrane transporters is highlighted by the large variety of substrates they transport, and by the observation that mutations in many of them cause heritable diseases in human. Likewise, overexpression of certain ABC transporters, such as P-glycoprotein and members of the multidrug resistance associated protein (MRP) family, is associated with multidrug resistance in various cells and organisms. Understanding the structure and molecular mechanisms of transport of the ABC transporters in normal tissues and their possibly altered function in human diseases requires large amounts of purified and active proteins. For this, efficient expression systems are needed. The methylotrophic yeast Pichia pastoris has proven to be an efficient and inexpensive experimental model for high-level expression of many proteins, including ABC transporters. In the present review, we will summarize recent advances on the use of this system for the expression, purification, and functional characterization of P-glycoprotein and two members of the MRP subfamily.
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PMID:Overexpression, purification, and functional characterization of ATP-binding cassette transporters in the yeast, Pichia pastoris. 1258 81

The effects of a series of pharmaceutical excipients, including Span 80, Brij 30, Tween 20, Tween 80, Myrj 52, and sodium lauryl sulfate (with increasing hydrophilic-lipophilic balance (HLB) values) on the intracellular accumulation, transport kinetics, and intestinal absorption of epirubicin were investigated in both the human colon adenocarcinoma (Caco-2) cell line and the everted gut sacs of rat jejunum and ileum. The possible use of these excipients as multidrug resistance (MDR) reversing agents also was examined. Epirubicin uptake experiments using a flow cytometer showed that these selected excipients markedly enhanced the intracellular accumulation of epirubicin in Caco-2 cells in a dose-dependent manner. The optimal effect on the epirubicin uptake was characteristic of excipients with intermediate HLB values ranging from 10 to 17. Moreover, the optimal net efficacy was observed for excipients with polyoxyethylene chains and intermediate chain length of fatty acid and fatty alcohol (monolaurate for Tween 20, monooleate for Tween 80, monostearate for Myrj 52, and lauryl alcohol for Brij 30). These excipients significantly increased apical to basolateral absorption and substantially reduced basolateral to apical efflux of epirubicin across Caco-2 monolayers. Furthermore, the addition of Tween 20, Tween 80, Myrj 52, and Brij 30 markedly enhanced mucosal to serosal absorption of epirubicin in the rat jejunum and ileum. This study suggests that inhibition of intestinal P-glycoprotein (P-gp), multidrug resistance associated protein family (MRPs), or other transporter proteins by pharmaceutical excipients may improve oral absorption of drugs in MDR spectrum. The optimal HLB values of surfactant systems with suitable hydrocarbon chains and polar groups are an important factor in designing promising epirubicin formulations for reversing MDR. In conclusion, therapeutic efficacy of epirubicin may be enhanced by the use of such low toxicity excipients as absorption enhancers and MDR modulators in formulations. This provides a potential strategy for improving bioavailability in the optimization of formulations for drugs performing intestinal absorption and secretion.
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PMID:Relationships between the hydrophilic-lipophilic balance values of pharmaceutical excipients and their multidrug resistance modulating effect in Caco-2 cells and rat intestines. 1276 5

Technetium-99m Tetrofsomin (Tc-TF) has been shown to be useful in identifying several types of tumors, such as breast, lung, and thyroid cancers. There was no report in the literature for Tc-TF uptake in hepatocellular carcinoma (HCC). The aim of this study was to evaluate the usefulness of Tc-TF liver imaging to detect HCC and investigate the relationship between Tc-TF liver imaging findings and P-glycoprotein (Pgp) and multidrug resistance associated protein (MRP) expression. Before any therapy, 22 patients with HCC were enrolled in this study. Tc-TF liver images were performed l0 minutes after intravenous injection of 20mCi Tc-TF. All patients had liver biopsy or surgery within l week after Tc-TF liver imaging. Immunohistochemical study of the biopsy or resected HCC specimens was performed using anti-human Pgp and MRP antibodies. Twenty of the 22 (90.9%) patients showed negative Tc-TF liver imaging results without significant Tc-TF uptake in HCC, whereas only the remaining 2 (9.1%) patients showed positive Tc-TF liver imaging results with significant Tc-TF uptake in HCC. Positive Pgp expression was observed in 13 of 20 patients with negative Tc-TF liver imaging results, whereas positive MRP expression was observed in 6 of the remaining 7 patients with negative both Tc-TF liver imaging results and Pgp expression. However, negative Pgp expression but positive MRP expression was observed in all of the remaining 2 patients with positive Tc-TF liver imaging results. The correlation between Tc-TF liver imaging findings and Pgp expression was significant and better than between Tc-TF liver imaging findings and MRP expression. Pgp or MRP expression in HCC may induce no significant Tc-TF uptake in HCC resulting in negative Tc-TF liver imaging findings. Therefore, Tc-TF liver imaging is potential to be a non-invasive method to predict Pgp or MRP expression in HCC. However, further studies with a larger series of patients and longer follow-up time are necessary to confirm our findings.
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PMID:Usefulness of technetium-99m tetrofosmin liver imaging to detect hepatocellular carcinoma and related to expression of P-glycoprotein or multidrug resistance associated protein-a preliminary report. 1283 84

Previous studies have demonstrated that doxorubicin (DOX) encapsulated in polyisohexylcyano-acrylate nanospheres (NS-DOX) circumvented the resistance of breast cancer cells overexpressing P-glycoprotein (Pgp). Another protein is involved in multidrug resistance phenotype, the multidrug resistance associated protein (MRP1). We report that NS-DOX overcomes multidrug resistance in breast cancer cells overexpressing MRP1. Taking into account that anthracyclines are conjugated to or co-transported with glutathione by MRP1, these data suggest that probably due to ion pair formation (NS-DOX), MRP1 could not transport the anthracycline. Pgp is probably able to transport the ion pair drug complex and the mechanisms of drug resistance reversion in Pgp expressing cells need to be further elucidated.
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PMID:Enhanced cytotoxicity and nuclear accumulation of doxorubicin-loaded nanospheres in human breast cancer MCF7 cells expressing MRP1. 1296 4


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