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)

MDR3 is a phospholipid translocator homologous to MDR1 P-glycoprotein. MDR3 localizes to the canalicular membrane and contributes to the secretion of bile. To elucidate the role of protein kinase C in the regulation of MDR3 gene expression, we investigated the effect of phorbol 12-myristate 13-acetate (PMA) on the level of MDR3 mRNA in human Chang liver cells by a reverse transcription-polymerase chain reaction method. The steady-state expression of MDR3 mRNA was decreased by PMA after treatment for 8-20 hr and at concentrations of 1-100 nM. PMA also decreased the doxorubicin-induced expression of MDR3 mRNA. 4alpha-Phorbol 12,13-didecanoate, a negative control compound, did not decrease the expression at these concentrations. The down-regulatory effect of PMA was partially suppressed by the protein kinase C inhibitors 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)maleimide (GF109203X) and calphostin C. Furthermore, cycloheximide, a protein synthesis inhibitor, antagonized the effect of PMA. From these results, it was suggested that the level of MDR3 mRNA was negatively regulated by a protein kinase C- and protein synthesis-dependent system and that the system regulated both the stable and inducible expression of MDR3 mRNA.
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PMID:Protein kinase C-mediated down-regulation of MDR3 mRNA expression in Chang liver cells. 1133 Oct 69

Human leukemia cells may acquire MDR1/P-glycoprotein-mediated multidrug resistance (MDR) in the course of short-term (within hours) exposure to many stress stimuli. This effect is thought to be associated with the activity of protein kinase C (PKC) (Chaudhary, Roninson, 1992. 1993). However, we show here that cytosine beta-D-arabinofuranoside (Ara C) and 12-O-tetradecanoylphorbol 13-acetate (TPA), agents that activated the MDR1 gene in the H9 T-cell leukemia line, caused different effects on PKC. Namely, TPA activated PKC whereas Ara C was without the effect. Furthermore, cell permeable ceramide, a lipid messenger known to mediate cellular effects of chemotherapeutic drugs and TPA, activated the MDR1 gene and down-regulated PKC. These results suggest that the MDR1 gene can be activated via the pathway(s) that requires PKC activity as well as via bypass of PKC. The redundancy of signaling pathways that regulate the acquisition of MDR should be taken into consideration for prevention of secondary drug resistance in hematological malignancies.
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PMID:Differential effects of the MDR1 (multidrug resistance) gene-activating agents on protein kinase C: evidence for redundancy of mechanisms of acquired MDR in leukemia cells. 1142 20

We have recently reported that the apical membrane of the proximal tubule S2 segment from wild-type mice (WT mice) has the capacity for P-glycoprotein- (P-gp-) mediated drug efflux, whereas mice in which both mdr1a and mdr1b genes are disrupted (KO mice) do not. To examine the intracellular regulatory mechanisms of drug-transporting P-gp activity, we isolated and perfused proximal tubule S2 segments from WT and KO mice, and measured luminal efflux of the intracellular fluorescence of rhodamine 123, a fluorescent substrate of P-gp. The decay half-time of the intracellular fluorescence (t1/2) was regarded as an index of the drug-transporting P-gp activity. In the WT mice, the t1/2 was 36+/-5 s (n=35) during the basal period, and was significantly increased to 440+/-45 s by the luminal addition of verapamil (an inhibitor of P-gp). The addition of phorbol 12-myristate 13-acetate (PMA) [a protein kinase C (PKC) activator] to the bath increased t1/2, but 4alpha-phorbol (the inactive form of PMA) did not. The PMA-induced increase in t1/2 was further increased by the luminal addition of verapamil, and was partially inhibited by co-treatment with staurosporine or H-7 (inhibitors of PKC). Pretreatment with wortmannin or LY294002 [inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase)] added to the bath also increased t1/2. The wortmannin- and LY294002-induced increase in t1/2 was also further increased by the luminal addition of verapamil. The effects of PMA on t1/2 were additive after cotreatment with wortmannin or LY294002. In the KO mice, t1/2 was 440+/-25 s (n=18) during the basal period, and was no longer affected by the addition of verapamil, staurosporine, H-7, wortmannin, or LY294002. Based on the use of pharmacological agents, we conclude that in the proximal tubule from WT mice, P-gp-mediated drug secretion occurs independently via PKC- and PI 3-kinase-dependent processes, whereas it is not present in KO mice, independently of PKC- and PI 3-kinase.
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PMID:Protein kinase C and phosphatidylinositol 3-kinase independently contribute to P-glycoprotein-mediated drug secretion in the mouse proximal tubule. 1148 61

We have developed and validated a sensitive and selective method for the determination of the P-glycoprotein modulator GF120918 in murine and human plasma. Chlorpromazine is used as internal standard. Sample pretreatment involves liquid-liquid extraction with tert-butyl methyl ether. Chromatographic separation is achieved by reversed-phase high-performance liquid chromatography using a Symmetry C18 column and detection was accomplished with a fluorescence detector set at excitation and emission wavelengths of 260 and 460 nm, respectively. The mobile phase consists of acetonitrile-50 mM ammonium acetate buffer, pH 4.2 (35:65, v/v). To achieve good separation from endogenous compounds and to improve the peak shape the counter-ion 1-octane sulfonic acid (final concentration 0.005 M) was added to the mobile phase. The lower limit of quantitation was 5.7 ng/ml using 200 microl of human plasma and 23 ng/ml using 50 microl of murine plasma. Within the dynamic range of the calibration curve (5.7-571 ng/ml) the accuracy was close to 100% and within-day and between-day precision were within the generally accepted 15% range. The stability of GF120918 was tested in plasma and blood from mice and humans incubated at 4 degrees C, room temperature, and 37 degrees C for up to 4 h. No losses were observed under these conditions. This method was applied to study the pharmacokinetics of orally administered GF120918 in humans and mice. The sensitivity of the assay was sufficient to determine the concentration in plasma samples obtained up to 24 h after drug administration.
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PMID:Bioanalysis and preliminary pharmacokinetics of the acridonecarboxamide derivative GF120918 in plasma of mice and humans by ion-pairing reversed-phase high-performance liquid chromatography with fluorescence detection. 1149 17

The effect of agosterol A, a novel polyhydroxylated sterol acetate isolated from a marine sponge, on P-glycoprotein (P-gp)-mediated multidrug-resistant cells (KB-C2) and the multidrug resistance associated protein (MRP1)-mediated multidrug-resistant cells (KB-CV60) was examined. Agosterol A reversed the resistance to colchicine in KB-C2 cells and also the resistance to vincristine in KB-CV60 cells at 3 to 10 microM concentration. Agosterol A at 3 mM increased the vincristine concentration in both KB-C2 cells and KB-CV60 cells to the level in parental KB-3-1 cells. Agosterol A also decreased the efflux of vincristine from both KB-C2 cells and KB-CV60 cells to the level seen in KB-3-1 cells. Agosterol A inhibited the [(3)H]azidopine-photolabeling of P-gp and also inhibited the uptake of [(3)H]S-(2,4-dinitrophenyl)glutathione (DNP-SG) in inside-out membrane vesicles prepared from KB-CV60 cells. We conclude that agosterol A directly inhibited drug efflux through P-gp and/or MRP1.
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PMID:Reversing effect of agosterol A, a spongean sterol acetate, on multidrug resistance in human carcinoma cells. 1150 22

P-glycoprotein (P-gp)/multi-drug resistance 1 (MDR1) gene is recognized to be, at least in part, responsible for the refractoriness to chemotherapy of leukemia. The transcriptional mechanism of MDR1 gene is largely unknown. However, recent reports have clarified that early growth response 1 gene (Egr1) positively regulates MDR1 transcription, while Wilms' tumor suppressor gene (WT1) does negative regulation of MDR1 gene expression in 12-O-tetradecanoylphorbol-13-acetate treated K562 cells. In addition, Egr1 and WT1 are structurally related transcription factors and bind to quite similar DNA sequences. Our study of mRNA expression profile of Egr1, WT1 and MDR1 in fresh AML samples demonstrated that there are disease-specific patterns. Egr1 mRNA was frequently and strongly expressed in monocytic leukemia cells, especially in AML M4 cells. WT1 mRNA was undetectable in t(8;21) AML cells. mRNA expression of MDR1 was frequent in AML M1 and t(8;21) AML cells, in which the expression level was highest in AML M1 and was low in monocytic leukemia (M4 and M5). Then, expression level of MDR1 was inversely correlated with Egr1. By liquid culture of leukemia cell lines and fresh AML cells with the addition of all-trans retinoic acid (ATRA), modulation of P-gp/MDR1 and Egr1 was observed and the pattern of modulation was divided into four groups: (1) blastic AML type, in which distinct expression of P-gp/MDR1 and CD34 was not influenced by ATRA; (2) t(8;21)AML type, in which P-gp/MDR1 expression was augmented by ATRA, while CD34 was kept high; (3) AML M3 type, in which P-gp/MDR1 expression was reduced with granulocytic differentiation by ATRA; (4) monocytic AML type, in which P-gp/MDR1 expression was augmented by ATRA, while CD34 expression decreased, and strong Egr1 expression was downregulated just prior to the augmentation of P-gp/MDR1 expression. WT1 expression was not influenced by the addition of ATRA in each group. Previous reports have suggested that P-gp/MDR1 plays an important role in resistance to chemotherapy, and is recognized as one of the stem cell marker. However, P-gp/MDR1 expression augmented by ATRA, which was observed in monocytic AML, was recognized as a functional molecule of mature monocyte/macrophage, because CD34 expression decreased and CD13 expression increased by ATRA. Finally, expression of P-gp/MDR1 in monocytic leukemia, which was functionally confirmed by Rh123 efflux study, was thought to be closely related to the characteristic modulation of Egr1 expression by ATRA.
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PMID:Augmented expression of P-gp/multi-drug resistance gene by all-trans retinoic acid in monocytic leukemic cells. 1173 1

The present study examined the role of protein kinase C (PKC) in the P-glycoprotein (P-gp)-induced modulation of regulatory volume increase (RVI) in the isolated nonperfused proximal tubule S2 segments from mice lacking both mdr1a and mdr1b genes (KO) and wild-type (WT) mice. The hyperosmotic solution (500 mosmol/kgH(2)O) involving 200 mM mannitol activated PKC and elicited RVI in the tubules from KO mice but not from WT mice. The addition of the hyperosmotic solution including the PKC activator phorbol 12-myristate 13-acetate (PMA) to the tubules of the WT mice activated PKC and elicited RVI. The hyperosmotic solution in the presence of the P-gp inhibitors (verapamil or cyclosporin A) elicited RVI in the tubules from the WT mice but not from the KO mice. The PMA- and the P-gp inhibitors-induced RVI was abolished by cotreatment with the PKC inhibitors (staurosporine or calphostin C). In the tubules of the KO mice, the PKC inhibitors abolished RVI, but PMA did not. In the tubules of the WT mice, the microtubule disruptor (colchicine), the microfilament disruptor (cytochalasin B), the phosphatidylinositol 3-kinase (PI 3-kinase) blocker (wortmannin), but not another PI 3-kinase blocker (LY-294002), inhibited the PMA-induced RVI. In the tubules of the KO mice, colchicine, cytochalsin B, and wortmannin abolished RVI, but LY-294002 did not. We conclude that 1) in the mouse proximal tubule, P-gp-induced modulation of RVI occurs via PKC; and 2) the microtubule, microfilament, and wortmannin-sensitive, LY-294002-insensitive PI 3-kinase contribute to the PKC-induced RVI.
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PMID:P-gp-induced modulation of regulatory volume increase occurs via PKC in mouse proximal tubule. 1173 14

The antihypertension agent iodoazidoaryl prazosin (IAAP) has been made using a convergent route involving addition of an acylated piperazine 7 to 2-chloroquinazoline 5. IAAP has been shown to function as a multidrug resistance (MDR) reversal agent and bind to P-glycoprotein, a transmembrane transport protein. A study is also reported involving palladium-catalyzed substitution with amine heterocycles. With N,N-bis(2,6-diisopropyl)dihydroimidazolium chloride (10) as the ligand (2 mol %) for palladium(II) acetate (2 mol %) in THF at room temperature, morpholine added to 5 in 81% yield.
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PMID:A modified synthesis of iodoazidoaryl prazosin. 1242 72

A sensitive high-performance liquid chromatographic (HPLC) method was developed for the determination of paclitaxel in micro-samples of rat plasma in order to study the mechanism of enhanced systemic exposure of paclitaxel co-administered with P-glycoprotein inhibitors. The assay involved solid-phase extraction procedures using 2'-methylpaclitaxel as the internal standard. Chromatographic separations were achieved using a ZORBAX ODS C18 column and mobile phase consisting of acetonitrile, methanol and ammonium acetate buffer (10 mM, pH 5.0) (48.5:16.5:35) pumped at 0.8 ml/min. The effluents were measured for UV absorption at 227 nm, with retention times of 8.5 and 11.0 min for paclitaxel and 2'-methylpaclitaxel, respectively. The chromatographic separation was excellent, with no endogenous interference. The standard curves showed a good linearity (r=0.9994) over the concentration ranges of 10-1,000 ng/ml. At 1,000 ng/ml, the absolute recoveries of paclitaxel and 2'-methylpaclitaxel are 89 and 90%, respectively. The intra- and inter-day variabilities of paclitaxel were both less than 15%. This validated method for the assay of paclitaxel in micro-sample rat plasma made it feasible to study the pharmacokinetics of the drug in a single rat.
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PMID:Quantitation of paclitaxel in micro-sample rat plasma by a sensitive reversed-phase HPLC assay. 1260 67

The taxanes, paclitaxel (PTX) and docetaxel (DTX), belong to a novel class of anticancer drugs that stabilize microtubules and lead to tumor cell death. While both agents are widely used for the treatment of lung, breast, and ovarian cancer, many tumor types are refractory or develop resistance to these drugs. We describe here a novel analogue of DTX, designated MAC-321 [Microtubule/Apoptosis/Cytotoxic: 5beta, 20-epoxy-1, 2alpha-, 4-, 7beta-, 10beta-, 13alpha-hexahydroxytax-11-en-9-one 4 acetate 2 benzoate 7-propionate 13-ester with (2R,3S)-N-tertbutoxycarbonyl-3-(2-furyl)isoserine], that overcomes P-glycoprotein-mediated resistance to PTX and DTX in preclinical model systems. Similar to PTX or DTX, MAC-321 enhanced the rate of tubulin polymerization in vitro and caused the bundling of microtubules in cells. MAC-321 inhibited proliferation of a panel of 14 tumor cell lines with minimal variation in potency (IC(50) = 2.2 +/- 1.4 nM; range = 0.6-5.3 nM). Unlike PTX or DTX, the IC(50) of MAC-321 did not vary in cells that expressed low to moderate levels of P-glycoprotein. Even under extraordinary conditions in KB-V1 cells, which highly overexpress P-glycoprotein, resistance to MAC-321 was 80-fold compared with that of PTX (1400-fold) and DTX (670-fold). In addition, equivalent or less resistance to MAC-321 compared with PTX or DTX was observed in four cell lines that contain distinct point mutations within the taxane-binding site of beta-tubulin. Most importantly, MAC-321 displayed superior in vivo efficacy because: (a) MAC-321 either partially or completely inhibited tumor growth in three tumor models that overexpressed P-glycoprotein and were resistant to PTX; and (b) unlike PTX or DTX, MAC-321 was highly effective when given orally. MAC-321 was also highly effective when given as single i.v. dose. Our findings suggest that MAC-321, which is currently under clinical evaluation, may have broad therapeutic value.
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PMID:MAC-321, a novel taxane with greater efficacy than paclitaxel and docetaxel in vitro and in vivo. 1455 6


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