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)

Prostate cancer has become the most common cancer in males and the second most common cause of male cancer death in England and Wales. Death rates have doubled over the last 20 years. Prostate cancer is characterized by a high initial response rate to hormonal therapy. Drug-resistance is a significant cause of relapse in cancer. The multidrug resistance genes (MDR) encode resistance to a diverse family of cytotoxic chemotherapy agents. There are four known MDR genes, two of which are present in humans. MDR1 encodes for P-glycoprotein, a 170-kDa transmembrane calcium-dependent efflux pump. We examined P-glycoprotein expression by immunocytochemistry in 96 patients with prostate cancer and 20 patients with benign prostatic hypertrophy. A direct correlate was found between tumor grade, stage, and prostate specific antigen levels, indicating the possible significance of this protein in recurrent prostate cancer.
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PMID:Expression of the multidrug resistance gene in human prostate cancer. 1076 19

A new type of organic Ca2+ channel blocker, tamolarizine, was examined for its reversing effect on multidrug-resistant tumor cells. Tamolarizine synergistically potentiated the cytotoxicity of doxorubicin for doxorubicin-resistant K562 cells (K562/DXR) at a concentration of 0.1-10 microM, but had hardly any synergistic effects in the parental cell line (K562) at the same concentration. Moreover, tamolarizine inhibits the P-glycoprotein pump-efflux activity in a dose-related manner and reduces the expression of the immunoreactive P-glycoprotein in K562/DXR cells as evaluated by cytofluorimetric assay. These results indicate that tamolarizine reverses the multidrug-resistance phenotype through direct interaction with P-glycoprotein.
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PMID:Reversal of multidrug resistance in human leukemia K562 by tamolarizine, a novel calcium antagonist. 1088 58

1. The combined effects of the macrolide antibiotics erythromycin, josamycin, clarithromycin and YM17K (3,4'-dideoxy mycaminosyl tylonolide hydrochloride) on in vitro intracellular accumulation of vinblastine or cyclosporine (Cs)A and on the in vivo antitumour activity of vinblastine were investigated using mouse leukaemia P388 cells (P388/S) and anticancer drug-resistant (P388/ADR) cells. These effects were compared with those of a calcium antagonist (verapamil) or immunosuppressants (FK506 and CsA). 2. All tested macrolide antibiotics increased the accumulation of both vinblastine and CsA in P388/ADR cells in a dose-dependent manner, but their potency was lower than that of verapamil, CsA or FK506. 3. When vinblastine (200 microg/kg) was administered intraperitoneally with each of the macrolide antibiotics (10 or 100 mg/kg) or with verapamil (25 mg/kg) once a day for 10 days in P388/ADR-bearing mice, combined effects of vinblastine with the macrolide antibiotics (erythromycin, clarithromycin and YM17K) or verapamil were observed. 4. The present study suggests that macrolide antibiotics may overcome anticancer drug resistance by inhibiting the binding of vinblastine or CsA to P-glycoprotein in P388/ADR cells. 5. We believe that these results are encouraging for combination chemotherapy to overcome P-glycoprotein-dependent anticancer drug-resistant tumours in clinical practice.
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PMID:Reversal of anticancer drug resistance by macrolide antibiotics in vitro and in vivo. 1090 87

Mibefradil, a calcium T- and L-channel blocker developed for use in hypertension, was recently removed from the market after reports of severe drug-drug interactions. Mibefradil is known to inhibit various cytochrome P450 enzymes involved in drug metabolism, particularly CYP3A. However, the extent and the severity of the observed drug interactions in humans suggest that inhibition of additional systems important to drug disposition, such as the drug transporter P-glycoprotein (P-gp), may also have contributed to the severity of the mibefradil interactions. A polarized epithelial cell line, LLC-PK1, which does not express P-gp, and the derived L-MDR1 cell line, which overexpresses human P-gp, were used to study the effects of mibefradil on drug transport. A markedly greater basal-to-apical versus apical-to-basal transport of [H3]mibefradil was seen in the L-MDR1, but not in the LLC-PK1 cells, suggesting that the drug is a substrate of P-gp. Using a human intestinal cancer-derived cell line Caco-2, which constitutively expresses P-gp, mibefradil was shown to be a potent inhibitor of P-gp-mediated digoxin transport, with an IC50 of 1.6 microM. Additionally, the effect of mibefradil on CYP3A was assessed using human liver microsomes. Mibefradil inhibited CYP3A-mediated nifedipine oxidase activity with an IC50 of 0.8 microM, and a Ki of 0.6 microM. Thus, mibefradil is not only a P-gp substrate, but also a potent inhibitor of both P-gp and CYP3A. These data suggest that the severity of drug interactions seen with mibefradil use is due to the dual inhibition of both P-gp and CYP3A.
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PMID:Mibefradil is a P-glycoprotein substrate and a potent inhibitor of both P-glycoprotein and CYP3A in vitro. 1090 97

Grapefruit juice, a beverage consumed in large quantities by the general population, is an inhibitor of the intestinal cytochrome P-450 3A4 system, which is responsible for the first-pass metabolism of many medications. Through the inhibition of this enzyme system, grapefruit juice interacts with a variety of medications, leading to elevation of their serum concentrations. Most notable are its effects on cyclosporine, some 1,4-dihydropyridine calcium antagonists, and some 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. In the case of some drugs, these increased drug concentrations have been associated with an increased frequency of dose-dependent adverse effects. The P-glycoprotein pump, located in the brush border of the intestinal wall, also transports many cytochrome P-450 3A4 substrates, and this transporter also may be affected by grapefruit juice. This review discusses the proposed mechanisms of action and the medications involved in drug-grapefruit juice interactions and addresses the clinical implications of these interactions.
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PMID:Drug-grapefruit juice interactions. 1099 29

The modulation of P-glycoprotein's (Pgp) ATPase activity and its ability to regulate swelling-activated 125I efflux, by PKC alpha and PKC epsilon, was examined in insect cells. Recombinant baculovirus was used to express human Pgp in Sf9 cells and Pgp was also coexpressed with either PKC alpha or PKC epsilon. ATPase assays showed the enzyme activity of Pgp to be elevated during co-expression with the Ca2+ dependent isoform PKC alpha, but not with the Ca2+ independent variant PKC epsilon. Furthermore, neither isoform, when co-expressed with Pgp, altered the swelling-activated efflux of 125I from Sf9 cells. However, in cells co-expressing Pgp/PKC (alpha or epsilon), pre-treatment with the phorbol ester TPA significantly reduced the swelling-activated 125I efflux with both PKC isoforms. Our results suggest that phosphorylation with the Ca2+ independent variant PKC epsilon does not regulate the ATPase activity of Pgp and that stimulation of PKC with TPA alters the swelling-activated efflux of anions from insect cells expressing Pgp.
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PMID:Selective modulation of P-glycoprotein's ATPase and anion efflux regulation activities with PKC alpha and PKC epsilon in Sf9 cells. 1105 26

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

The structure activity relationships were studied on newly synthesized 1,4-dihydropyridine derivatives possessing a 1-pentyl group at the 4-position, and 3-pyridylpropylester was found to be one of the effective fragments for overcoming P-glycoprotein mediated multidrug-resistance (MDR) in cultured human cancer cells, in vitro. 3-Pyridylpropylester was also found to be one of the effective fragments for increasing the life span of P-glycoprotein overexpressing MDR P388 leukemia-bearing mice, in vivo. All compounds had weak calcium antagonistic activities, but there appeared no relationship between MDR reversing effect and calcium antagonistic activity.
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PMID:Synthesis and structure--activity analysis of novel dihydropyridine derivatives to overcome multidrug resistance. 1120 76

The inhibition of the Na+/K+-ATPase by cardiotonic drugs like ouabain deeply perturbs both the properties of the cell membrane and the ionic composition of the cytoplasm and hence alters fundamental cell reactions. These three types of reactions may be involved in the stimulation of multidrug resistance 1 (MDR-1) gene expression and the synthesis of permeability glycoprotein [P-glycoprotein (P-gp)]. We have determined whether ouabain, which binds to an extracellular motif of the Na+/K+-ATPase, stimulates MDR-1 gene expression by measuring both mRNA and protein and whether the resulting P-gp extrudes hydrophobic compounds and causes resistance to antimitotic agents. The experiments were performed on Calu-3 cells, a human cell line from a pulmonary carcinoma. Northern blotting showed that treating the cells with submicromolar concentrations of ouabain stimulated MDR-1 gene expression within 24 h. The ouabain-induced stimulation of MDR-1 expression was not restricted to Calu-3 cells but also occurred in human carcinomatous colon (T-84 and HT-29) and hepatic (H7V3) cells. However, it is not ubiquitous because it was not found in HeLa cells. The stimulation was reproduced by other Na+/K+-ATPase inhibitors and occurred via enhanced gene transcription, apparently due to the increased cytosolic calcium concentration. Ouabain also increased the membrane content of P-gp, as detected by immunoblotting and immunohistology. We have developed a microvideo assay based on the properties of acetoxymethyl ester calcein and calcein to show that this P-gp extruded the hydrophobic acetoxymethyl ester calcein. Ouabain also caused the Calu-3 cells to become resistant to doxorubicin and vinblastine. Thus, although ouabain acts extracellularly, it may stimulate MDR-1 gene expression and P-gp synthesis and make cells resistant to hydrophobic cytotoxic compounds.
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PMID:Drug resistance induced by ouabain via the stimulation of MDR1 gene expression in human carcinomatous pulmonary cells. 1124 85

Multidrug resistance to chemotherapy is a major obstacle in the treatment of cancer patients. The best characterised mechanism responsible for multidrug resistance involves the expression of the MDR-1 gene product, P-glycoprotein. However, the resistance process is multifactorial. Studies of multidrug resistance mechanisms have relied on the analysis of cancer cell lines that have been selected and present cross-reactivity to a broad range of anticancer agents. This work characterises a multidrug resistant cell line, originally selected for resistance to the Vinca alkaloid vincristine and derived from the human erythroleukaemia cell K562. This cell line, named Lucena 1, overexpresses P-glycoprotein and have its resistance reversed by the chemosensitisers verapamil, trifluoperazine and cyclosporins A, D and G. Furthermore, we demonstrated that methylene blue was capable of partially reversing the resistance in this cell line. On the contrary, the use of 5-fluorouracil increased the resistance of Lucena 1. In addition to chemotherapics, Lucena 1 cells were resistant to ultraviolet A radiation and hydrogen peroxide and failed to mobilise intracellular calcium when thapsigargin was used. Changes in the cytoskeleton of this cell line were also observed.
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PMID:Multidrug resistance in tumour cells: characterization of the multidrug resistant cell line K562-Lucena 1. 1124 70


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