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 have established a human myelogenous leukemia cell line (HL60/AD) that is 10-fold cross-resistant to both 1-beta-D-arabinofuranosylcytosine (ara-C) and daunorubicin; the cell line was isolated from HL60 by simultaneous treatment with these two agents at low drug concentrations attainable in clinical trials. HL60/AD was found to have multiple resistance mechanisms. With regard to ara-C, HL60/AD cells showed decreased deoxycytidine kinase activity but did not show elevation of cytidine deaminase activity or a decrease in ara-C influx. With regard to daunorubicin, a decrease in topoisomerase II activity was found. A decrease in intracellular accumulation of daunorubicin was also found. P-glycoprotein was not detected, but the multidrug resistance-associated protein was expressed. Furthermore, an increase of total cellular glutathione (GSH) content was found. Interestingly, the resistance of HL60/AD cells not only to daunorubicin but also to ara-C was markedly reversed by treatment with L-buthionine-(S,R)-sulfoximine (BSO), a potent inhibitor of GSH synthesis. After exposure of HL60/AD to ara-C, mitochondrial membrane potential and reactive oxygen intermediates showed no significant change, but a considerable loss of mitochondrial membrane potential and an increase in reactive oxygen intermediate generation were caused by pre-incubation with BSO. Neither elevation of GSH nor reversal of resistance by BSO was found in ara-C-resistant HL60 cells that were selected only with ara-C. These findings suggest that in addition to the summation of the mechanisms of resistance to each agent reported previously, an increased level of GSH plays an important role in the cross-resistance induced in HL60/AD cells by simultaneous exposure to both drugs.
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PMID:Simultaneous treatment with 1-beta-D-arabinofuranosylcytosine and daunorubicin induces cross-resistance to both drugs due to a combination-specific mechanism in HL60 cells. 1119 56

Small hydrophobic peptides were studied as possible substrates of the multidrug resistance protein (MRP)-1 (ABCC1) transmembrane transporter molecule. As observed earlier for P-glycoprotein- (Pgp; ABCB1) overexpressing cells, MRP1-overexpressing cells, including cells stably transfected with the MRP1 cDNA, showed distinct resistance to the cytotoxic peptide N-acetyl-Leu-Leu-norleucinal (ALLN). Resistance to this peptide and another toxic peptide derivative, which is based on a Thr-His-Thr-Nle-Glu-Gly backbone conjugated to butyl and benzyl groups (4A6), could be reversed by MRP1 inhibitors. The reduced toxicity of 4A6 in MRP1-overexpressing cells was found to be associated with lower accumulation of a fluorescein-labeled derivative of this peptide. Glutathione (GSH) depletion had a clear effect on resistance to ALLN but hardly affected 4A6 resistance. In a limited structure-activity study using peptides that are analogous to 4A6, MRP1-overexpressing cells were found to be resistant to these peptides as well. Remarkably, when selecting A2780 ovarian cancer cells for resistance to ALLN, even in the absence of Pgp blockers, resulting cell lines had up-regulated MRP1, rather than any of the other currently known multidrug resistance transporter molecules including Pgp, MRP2 (ABCC2), MRP3 (ABCC3), MRP5 (ABCCS), and the breast cancer resistance protein ABCG2. ALLN-resistant, MRP1-overexpressing cells were found to be cross-resistant to 4A6 and the classical multidrug resistance drugs doxorubicin, vincristine, and etoposide. This establishes MRP1 as a transporter for small hydrophobic peptides. More extensive structure-activity relationship studies should allow the identification of clinically useful peptide antagonists of MRP1.
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PMID:Peptide transport by the multidrug resistance protein MRP1. 1128 30

MRP1 is a 190-kDa membrane glycoprotein that confers multidrug resistance (MDR) to tumor cells. MRP1 is characterized by an N-terminal transmembrane domain (TMD(0)), which is connected to a P-glycoprotein-like core region (DeltaMRP) by a cytoplasmic linker domain zero (L(0)). It has been demonstrated that GSH plays an important role in MRP1-mediated MDR. However, the mechanism by which GSH mediates MDR and the precise roles of TMD(0) and L(0) are not known. We synthesized [(125)I]11-azidophenyl agosterol A ([(125)I]azidoAG-A), a photoaffinity analog of the MDR-reversing agent, agosterol A (AG-A), to photolabel MRP1, and found that the analog photolabeled the C-proximal molecule of MRP1 (C(932-1531)) in a manner that was GSH-dependent. The photolabeling was inhibited by anticancer agents, reversing agents and leukotriene C(4). Based on photolabeling studies in the presence and absence of GSH using membrane vesicles expressing various truncated, co-expressed, and mutated MRP1s, we found that L(0) is the site on MRP1 that interacts with GSH. This study demonstrated that GSH is required for the binding of an unconjugated agent to MRP1 and suggested that GSH interacts with L(0) of MRP1. The photoanalog of AG-A will be useful for identifying the drug binding site within MRP1, and the role of GSH in transporting substrates by MRP1.
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PMID:Glutathione-dependent binding of a photoaffinity analog of agosterol A to the C-terminal half of human multidrug resistance protein. 1130 32

Multidrug resistance P-glycoprotein 2 (Mdr2) is a phospholipid translocator in the canalicular membrane that is essential for the formation of biliary phospholipid vesicles and mixed lipid/bile salt micelles. Incorporation into biliary vesicles and micelles is thought to contribute to the hepatobiliary excretion of certain hydrophobic organic anions, such as indocyanine green (ICG). The present studies characterized the biliary excretion of two hydrophobic organic anions, ICG and estradiol-17beta(beta-D-glucuronide) (E(2)17G), in the single-pass isolated perfused liver and the biliary excretion of glutathione (GSH) in vivo in wild-type and Mdr2-/- female mice. The biliary excretion of ICG (0.4 micromol) was reduced by 90%, while the biliary excretion of total GSH was decreased by 65% in Mdr2-/- mice relative to wild-type mice. In contrast, the biliary excretion of E(2)17G (0.1 micromol) was increased by 30% in Mdr2-/- mice. These data indicate that the absence of Mdr2 differentially influences the biliary excretion of these organic anions and suggest that phospholipid vesicles and mixed micelles in bile are essential for the biliary excretion of ICG.
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PMID:Multidrug resistance p-glycoprotein 2 is essential for the biliary excretion of indocyanine green. 1130 27

Multidrug resistance is a major obstacle for the successful use of chemotherapy. The multidrug resistance phenotype is often attributed to overexpression of P-glycoprotein, which is an energy-dependent drug efflux pump. We investigated a new strategy to overcome multidrug resistance, using purified bovine serum amine oxidase, which generates two major toxic products from the polyamine spermine. The cytotoxicity of the aldehyde(s) and H2O2, produced by the enzymatic oxidation of micromolar concentrations of spermine, was evaluated in multidrug resistant Chinese hamster ovary cells CHRC5 with overexpression of P-glycoprotein, using a clonogenic cell survival assay. We examined the ability of hyperthermia (42 degrees C), and inhibition of cellular detoxification systems, to sensitize multidrug resistant cells to spermine oxidation products. Severe depletion of intracellular glutathione was achieved using L-buthionine sulfoximine and inhibition of glutathione S-transferase by ethacrynic acid. CH(R)C5 cells showed no resistance to the toxic oxidation products of spermine, relative to drug-sensitive AuxB1 cells. Exogenous catalase protected cells against cytotoxicity of H2O2, but spermine-derived aldehyde(s) still caused some cytotoxicity. Hyperthermia (42 degrees C) enhanced cytotoxicity of spermine oxidation products. Cytotoxic responses in CH(R)C5 cells were compared to the drug-sensitive cells, to determine whether there are differential responses. CH(R)C5 cells were more sensitive to the cytotoxic effect of spermine oxidation products under more extreme conditions (higher temperature, higher spermine concentration, and longer exposure time). Glutathione depletion or glutathione S-transferase inhibition also led to enhanced cytotoxicity of spermine oxidation products in CH(R)C5 and AuxB1 cells. Our findings suggest that hyperthermia, combined with toxic oxidation products generated from spermine and amine oxidase, could be useful for eliminating drug-sensitive and multidrug resistant cells.
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PMID:Amine oxidase, spermine, and hyperthermia induce cytotoxicity in P-glycoprotein overexpressing multidrug resistant Chinese hamster ovary cells. 1131 May 64

The histidine-rich protein 2 (PfHRP2) of Plasmodium falciparum has been implicated in the detoxification of ferriprotoporphyrin IX (FP) moieties that are produced as by-products of the digestion of haemoglobin. In this work, we have used a spectroscopic analysis to confirm that recombinant PfHRP2 binds FP. A monoclonal antibody that recognises both recombinant and authentic PfHRP2 was used in immunofluorescence microscopy studies. We found that PfHRP2 is mainly located in the erythrocyte cytosol of infected erythrocytes, however, dual labelling studies suggest that the location of a sub-population of the PfHRP2 molecules overlaps with that of the food vacuole-associated protein, P-glycoprotein homologue (Pgh-1). A semi-quantitative analysis of the level of PfHRP2 in infected erythrocytes suggests a concentration of a few micromolar in the food vacuole. Under conditions designed to mimic the parasite food vacuole, we found that 1.2 microM PfHRP2 is sufficient to catalyse the conversion of about 30% of a 100 microM sample of FP to beta-haematin within 24 h. Moreover, PfHRP2 is capable of promoting the H(2)O(2)-induced degradation of FP at pH 5.2. PfHRP2 also efficiently enhances the ability of FP to catalyse the H(2)O(2)-mediated oxidation of the model co-factor, ortho-phenylene diamine (OPD). These data suggest that PfHRP2 may promote the detoxification of FP and reactive oxygen species within the food vacuole. By contrast, PfHRP2 inhibits the destruction of FP by glutathione (GSH) at pH 7.4. This suggests that PfHRP2 is not a catalyst of FP degradation outside the food vacuole.
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PMID:Histidine-rich protein 2 of the malaria parasite, Plasmodium falciparum, is involved in detoxification of the by-products of haemoglobin degradation. 1137 42

We have recently demonstrated that RLIP76, a Ral-binding GTPase activating protein mediates ATP-dependent transport of glutathione (GSH) conjugates of electrophiles (GS-E) as well as doxorubicin (DOX), and that it is identical with DNP-SG ATPase, a GS-E transporter previously characterized by us in erythrocyte membranes (Awasthi et al. Biochemistry 39, 9327-9334). Multidrug resistance-associated protein (MRP1) belonging to the family of the ABC-transporters has also been suggested to be a GS-E transporter in human erythrocytes. Using immunological approaches, the present studies were designed to elucidate the relative contributions of RLIP76, MRP1, and P-glycoprotein (Pgp), in the ATP-dependent transport of GS-E and DOX in human erythrocytes. In Western blot analyses using antibodies against RLIP76, a strong expression of RLIP76 was observed in erythrocytes. Immunohistochemical studies using a fluorescent probe showed association of RLIP76 with erythrocyte membrane, which was consistent with its transport function. Neither MRP1 nor Pgp were detected in erythrocytes when the antibodies against MRP1 or Pgp were used. In erythrocyte inside-out vesicles (IOVs) coated with antibodies against RLIP76, a dose-dependent inhibition of the ATP-dependent transport of DOX and GS-E, including S-(dinitrophenyl)glutathione (DNP-SG), leukotriene C(4), and the GSH conjugate of 4-hydroxynonenal, was observed with a maximal inhibition of about 70%. On the contrary, in the IOVs coated with the antibodies against MRP1 or Pgp no significant inhibition of the ATP-dependent transport of these compounds was observed. These findings suggest that RLIP76 is the major ATP-dependent transporter of GS-E and DOX in human erythrocytes.
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PMID:RLIP76 is the major ATP-dependent transporter of glutathione-conjugates and doxorubicin in human erythrocytes. 1143 48

The human multidrug-resistance (MDR1) P-glycoprotein (Pgp) is an ATP-binding-cassette transporter (ABCB1) that is ubiquitously expressed. Often its concentration is high in the plasma membrane of cancer cells, where it causes multidrug resistance by pumping lipophilic drugs out of the cell. In addition, MDR1 Pgp can transport analogues of membrane lipids with shortened acyl chains across the plasma membrane. We studied a role for MDR1 Pgp in transport to the cell surface of the signal-transduction molecule platelet-activating factor (PAF). PAF is the natural short-chain phospholipid 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine. [(14)C]PAF synthesized intracellularly from exogenous alkylacetylglycerol and [(14)C]choline became accessible to albumin in the extracellular medium of pig kidney epithelial LLC-PK1 cells in the absence of vesicular transport. Its translocation across the apical membrane was greatly stimulated by the expression of MDR1 Pgp, and inhibited by the MDR1 inhibitors PSC833 and cyclosporin A. Basolateral translocation was not stimulated by expression of the basolateral drug transporter MRP1 (ABCC1). It was insensitive to the MRP1 inhibitor indomethacin and to depletion of GSH which is required for MRP1 activity. While efficient transport of PAF across the apical plasma membrane may be physiologically relevant in MDR1-expressing epithelia, PAF secretion in multidrug-resistant tumours may stimulate angiogenesis and thereby tumour growth.
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PMID:Multidrug-resistance P-glycoprotein (MDR1) secretes platelet-activating factor. 1146 58

We established several in vitro drug-resistant cell lines after continuous, long-term exposure of each drug to elucidate mechanisms of drug resistance. Whether drug resistance in these in vitro resistant cell lines reflects clinical drug resistance still remains unanswered. In this study, a pair of lung cancer cell lines was established from one patient with squamous cell carcinoma of the lung, with one line being established before and one line after combination chemotherapy (cisplatin/ifosfamide/vindesine). Combination chemotherapy selected resistant EBC-2/R cells, which showed cross-resistance to 4-hydroxyifosfamide (3.2-fold), cisplatin (2.3-fold), and methotrexate (3.7-fold) and collateral sensitivity to vindesine (0.77-fold) compared with parent EBC-2 cells. EBC-2/R cells showed decrease in intracellular accumulation of cisplatin, increase in intracellular concentration of glutathione (GSH), and overexpression of multidrug resistance-associated protein (MRP) 3 when compared with EBC-2 cells. A single cycle of chemotherapy was not sufficient to select other mechanisms of drug resistance, such as multidrug resistance-1/P-glycoprotein, MRPs 1, 2, 4, and 5, lung resistance-related protein, metallothionein IIa, glutathione S-transferase pi, gamma-glutamylcysteine synthetase (light and heavy chain), and excision repair cross complementing 1. Sequentially we established two cell lines, which cell lines showed the differences of the cisplatin resistance, expression level of MRP3, intracellular GSH level and intracellular accumulation of cisplatin. A pair of cell lines will be useful to elucidate resistant mechanisms of cisplatin in heterogeneous lung cancer cells.
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PMID:Characterization of non-small-cell lung cancer cell lines established before and after chemotherapy. 1184 6

The resistance of human malignancy to multiple chemotherapeutic agents ts remains a major obstacle in cancer therapy. This resistance phenomenon is called "multiple" because when cells are resistant they fail to respond to any of a wide range of anticancer agents. This leads to a complete ineffectiveness of any treatment and has dramatic consequences for the patients. This chemoresistance can be intrinsic--when tumour cells do not respond initially to the treatment--or acquired--when resistance appear during the therapy. Our understanding of the mechanisms responsible of the drug resistance has increased over the past few years. The tumour resistance is able to develop several strategies to inactivate the chemotherapeutic agents such as activation of the detoxification process, and overexpression of efflux pump proteins. The phenotype resistance of the cell is mainly characterised by an increased expression of membrane transport proteins such as the P-glycoprotein and the Multidrug Resistance Protein--MRPI--that act as real efflux pump to anticancer agent and contribute to physiological alterations i.e. intracellular pH and plasma membrane potentials. The detoxification procedure is also implicated with the Glutathione S transferase enzymes and the major anti oxidant of the cells the glutathione (GSH). More recently a newly reported transporter called "Breast Resistance Cancer Protein" has appeared. The role of all these transporters and the link with the detoxification systems in the clinical outcome of cancer chemotherapy is the subject of intense research. Particularly, one way of interest concerned in vivo investigations with radiolabelled compounds used in nuclear medicine. The understanding of how the radiolabelled compounds could interact with the phenotype resistance of the cells had a key role for further exploration of molecular imaging of the MDR phenotype.
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PMID:The multidrug resistance mechanisms and their interactions with the radiopharmaceutical probes used for an in vivo detection. 1187 78


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