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)

The effect of atovarstatin on digoxin pharmacokinetics was assessed in 24 healthy volunteers in two studies. Subjects received 0.25 mg digoxin daily for 20 days, administered alone for the first 10 days and concomitantly with 10 mg or 80 mg atorvastatin for the last 10 days. Mean steady-state plasma digoxin concentrations were unchanged by administration of 10 mg atorvastatin. Mean steady-state plasma digoxin concentrations following administration of digoxin with 80 mg atorvastatin were slightly higher than concentrations following administration of digoxin alone, resulting in 20% and 15% higher Cmax and AUC(0-24) values, respectively. Since tmax and renal clearance were not significantly affected, the results are consistent with an increase in the extent of digoxin absorption in the presence of atorvastatin. Digoxin is known to undergo intestinal secretion mediated by P-glycoprotein. Since atorvastatin is a CYP3A4 substrate and many CYP3A4 substrates are also substrates for P-glycoprotein transport, the influence of atorvastatin and its metabolites on P-glycoprotein-mediated digoxin transport in monolayers of the human colon carcinoma (Caco-2) cell line was investigated. In this model system, atorvastatin exhibited efflux or secretion kinetics with a K(m) of 110 microM. Atorvastatin (100 microM) inhibited digoxin secretion (transport from the basolateral to apical aspect of the monolayer) by 58%, equivalent to the extent of inhibition observed with verapamil, a known inhibitor of P-glycoprotein transport. Thus, the increase in steady-state digoxin concentrations produced by 80 mg atorvastatin coadministration may result from inhibition of digoxin secretion into the intestinal lumen.
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PMID:Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion. 1063 27

OC144-093 is a novel substituted diarylimidazole (Mr 495) generated using the OntoBLOCK system, a solid-phase combinatorial chemistry technology, in combination with high-throughput cell-based screening. OC144-093 reversed multidrug resistance (MDR) to doxorubicin, paclitaxel, and vinblastine in human lymphoma, breast, ovarian, uterine, and colorectal carcinoma cell lines expressing P-glycoprotein (P-gp) with an average EC50 of 0.032 microM. Inhibition of MDR by OC144-093 was reversible, but the effect persisted for at least 12 h after removal of compound from the culture medium. OC144-093 had no effect on the response to cytotoxic agents by cells in vitro lacking P-gp expression or expressing a multidrug resistance-associated protein (MRP-1). OC144-093 was not cytotoxic by itself against 15 normal, nontransformed, or tumor cell lines, regardless of P-gp status, with an average cytostatic IC50 of >60 microM. OC144-093 blocked the binding of [3H]azidopine to P-gp and inhibited P-gp ATPase activity. The compound was >50% p.o. bioavailable in rodents and dogs and did not alter the plasma pharmacokinetics of i.v.-administered paclitaxel. OC144-093 increased the life span of doxorubicin-treated mice engrafted with MDR P388 leukemia cells by >100% and significantly enhanced the in vivo antitumor activity of paclitaxel in MDR human breast and colon carcinoma xenograft models, without a significant increase in doxorubicin or paclitaxel toxicity. The results demonstrate that OC144-093 is an orally active, potent, and nontoxic inhibitor of P-gp-mediated multidrug resistance that exhibits all of the desired properties for treatment of P-gp-mediated MDR, as well as for prevention of MDR prior to selection and/or induction of refractory disease.
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PMID:Discovery and characterization of OC144-093, a novel inhibitor of P-glycoprotein-mediated multidrug resistance. 1085 Apr 44

We have obtained a novel multidrug resistant cell line, derived from HT29 G(+) human colon carcinoma cells, by selection with gradually increasing concentrations of the anti-mitotic, microtubule-disrupting agent colchicine. This HT29(col) cell line displayed a 25-fold increase in colchicine resistance and exhibited cross-resistance to doxorubicin, VP16, vincristine and taxol. Immunoblotting, combined with RT-PCR showed that the multidrug resistance phenotype was conferred by specific overexpression of the multidrug resistance protein 1. Confocal scanning laser microscopy revealed that multidrug resistance protein 1 specifically localized in the plasma membrane of HT29(col) cells. In a functional assay, using the fluorescent multidrug resistance protein 1 substrate 5-carboxyfluorescein, an increased efflux activity of HT29(col) cells was measured, as compared to the wild-type HT29 G(+) cells. MK571, a specific inhibitor of multidrug resistance protein 1, blocked the 5-carboxyfluorescein efflux, but only partially reversed resistance to colchicine, indicating that additional multidrug resistance mechanisms operate in HT29(col) cells. In conclusion, these results show for the first time overexpression of a functional multidrug resistance protein 1 under colchicine pressure, indicating that colchicine is not a P-glycoprotein-specific substrate. Colchicine-induced overexpression of multidrug resistance protein 1 is accompanied by a changed sphingolipid composition, i.e., enhanced levels of glucosylceramide and galactosylceramide. In addition, ceramide, a lipid messenger molecule involved in apoptosis-related signal transduction processes, was much more abundant in HT29(col) cells, which is indicative of a stress response.
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PMID:Differential expression of sphingolipids in MRP1 overexpressing HT29 cells. 1086 70

The brain distribution of the enantiomers of the antimalarial drug mefloquine is stereoselective according to the species. This stereoselectivity may be related to species-specific differences in the properties of some membrane-bound transport proteins, such as P-glycoprotein (P-gp). The interactions of racemic mefloquine and its individual enantiomers with the P-glycoprotein efflux transport system have been analysed in immortalised rat brain capillary endothelial GPNT cells. Parallel studies were carried out for comparison in human colon carcinoma Caco-2 cells. The cellular accumulation of the P-glycoprotein substrate, [(3)H]vinblastine, was significantly increased both in GPNT cells and in Caco-2 cells when treated with racemic mefloquine and the individual enantiomers. In GPNT cells, the (+)-stereoisomer of mefloquine was up to 8-fold more effective than its antipode in increasing cellular accumulation of [(3)H]vinblastine, while in Caco-2 cells, both enantiomers were equally effective. These results suggest that racemic mefloquine and its enantiomers are effective inhibitors of P-gp. Furthermore, a stereoselective P-glycoprotein inhibition is observed in rat cells but not in human cells. The efflux of [(14)C]mefloquine from GPNT cells was decreased when the cells were incubated with the P-gp modulators, verapamil, cyclosporin A or chlorpromazine, suggesting that MQ could be a P-gp substrate.
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PMID:Interactions of racemic mefloquine and its enantiomers with P-glycoprotein in an immortalised rat brain capillary endothelial cell line, GPNT. 1111 70

Resistance to multiple drugs is mediated by lung resistance-related protein (LRP) as well as P-glycoprotein (P-gp) and multidrug resistance protein (MRP). The levels of expression of LRP mRNA and LRP in a human colon carcinoma cell line, SW-620, were increased by the differentiation-inducing agent, sodium butyrate (NaB). Treatment of SW-620 cells with NaB for 2 weeks conferred resistance to adriamycin (ADM) and VP-16. The resistance was almost completely reversed by PAK-104P, a pyridine analog, but not by cepharanthine. ADM accumulated mainly in the nuclei of SW-620 cells not treated with NaB and in the cytoplasm of SW-620 cells treated with NaB. When the NaB-treated SW-620 cells were incubated with ADM in the presence of PAK-104P, the accumulation of ADM in nuclei was substantially increased. Isolated nuclei from untreated cells accumulated more ADM than nuclei from NaB-treated cells. Efflux of ADM from the nuclei isolated from NaB-treated cells was enhanced. PAK-104P and an antibody against LRP increased the accumulation of ADM in the isolated nuclei from NaB-treated cells, and inhibited the enhanced efflux of ADM from the nuclei. These findings suggest that at least in part, PAK-104P reverses LRP-mediated drug resistance by inhibiting the efflux of ADM from nuclei. PAK-104P may be useful for reversing MDR in tumors that overexpress LRP.
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PMID:Reversal of LRP-associated drug resistance in colon carcinoma SW-620 cells. 1114 11

Intestinal P-glycoprotein, which is encoded by the MDR1 gene, plays an important role in the absorption and presystemic elimination of many xenobiotics. Hence, an understanding of the factors regulating its expression and function is of substantial interest. In addition to genetic factors, exposure to drugs such as rifampin can profoundly affect its expression. So far, the mechanisms by which rifampin induces MDR1 expression are poorly understood. Recent studies demonstrate that the nuclear receptor PXR (pregnane X receptor) is involved in xenobiotic induction of CYP3A4. Because CYP3A4 and MDR1 are often co-induced, we investigated whether a similar mechanism is also involved in MDR1 induction. The human colon carcinoma cell line LS174T was used as an intestinal model to study induction because in these cells the endogenous MDR1 gene is highly inducible by rifampin. The 5'-upstream region of human MDR1 was examined for the presence of potential PXR response elements. Several binding sites were identified that form a complex regulatory cluster at about -8 kilobase pairs. Only one DR4 motif within this cluster is necessary for induction by rifampin. We conclude that induction of MDR1 is mediated by a DR4 motif in the upstream enhancer at about -8 kilobase pairs, to which PXR binds.
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PMID:Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. 1129 22

BN 80915 is the lead compound from a novel class of E-ring modified camptothecin analogues, the homocamptothecins, which show potent antitumor activities in animal models. Here, we report that BN 80915 induces up to 2-fold more cleavable complexes between plasmid DNA and purified human topoisomerase I than SN-38 and camptothecin. BN 80915 also induces DNA-topoisomerase I complexes in living HT-29 colon carcinoma cells, as shown by the in vivo link assay. BN 80915 is an extremely potent inducer of DNA-protein complexes in these cells starting at a concentration of 5 nM in the media. BN 80915 is clearly more potent than SN-38, because at least 20 times more SN-38 is needed to induce comparable levels of cleavable complexes. Kinetic experiments show that BN 80915 induces cleavable complexes within minutes that remain stable for at least 6 h in the presence of drug. Whereas the majority of the complexes are reversed within 15 min after drug removal, a substantial fraction (30%) persists for at least 4 h, in contrast with SN-38-treated cells, where all complexes have disappeared by this time. BN 80915 shows strong antiproliferative effects toward HT-29 cells with an IC50 of 0.3 nM compared with 20 nM for SN-38 and 40 nM for topotecan. BN 80915 is also potent against other colon carcinoma cells as well as toward cells growing in three dimensions as multicellular spheroids. HL-60 cells expressing functional P-glycoprotein or multidrug resistance protein show no cross-resistance toward BN 80915. Taken together, our results show that BN 80915 is unusually potent toward human colon carcinoma cells because of the formation of high levels of stable, covalent DNA-topoisomerase complexes.
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PMID:Unusual potency of BN 80915, a novel fluorinated E-ring modified camptothecin, toward human colon carcinoma cells. 1130 74

The antitumor cryptophycins are synthetic derivatives of the desipeptide cryptophycins isolated from the cyanobacterium Nostoc sp. Cryptophycin 52 that is currently in clinical trial in solid tumors, is prepared by total synthesis of four key fragments that are coupled to form the final product. The mechanism of anticancer activity of the cryptophycins has been associated with their destabilization of microtubules and with their induction of bcl-2 phosphorylation leading to apoptosis. The cryptophycins maintain activity against ovarian and breast carcinoma cells that overexpress the multidrug resistance efflux pump P-glycoprotein. Cryptophycin 52 has demonstrated a broad range of antitumor activity against both murine and human tumors. In the human MX-1 breast carcinoma xenograft cryptophycin 55 produced greater-than- additive tumor response in combination with 5-fluorouracil. In human non-small cell lung carcinoma and human small cell carcinoma xenografts, administration of the cryptophycins along with gemcitabine, cisplatin or carboplatin resulted in antitumor activity greater than either agent alone. The cryptophycins appear to be additive with fractionated radiation therapy in the human H460 non-small cell lung carcinoma. In the human HCT116 colon carcinoma, the cryptophycins resulted in a greater than additive tumor response when administered sequentially with 5-fluorouracil or irinotecan. Treatment of animals bearing intraperitoneal human OVCAR-2 ovarian carcinoma with cryptophycin 52 resulted in survival times that were greater than those achieved with docetaxel or paclitaxel. Cryptophycin 52 is currently in early clinical testing.
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PMID:Cryptophycins: a novel class of potent antimitotic antitumor depsipeptides. 1147 66

We selected a mitoxantrone-resistant HT29 colon carcinoma cell line (HT29/MIT) that exhibited a very high degree of resistance to the selecting agent and marked resistance to topotecan and SN38, but limited resistance to doxorubicin. The development of drug resistance was independent of expression of P-glycoprotein or multidrug resistance-associated protein but was associated with high up-regulation of the breast carcinoma resistance protein (BCRP) as shown by Western blot analysis. BCRP overexpression was associated with a reduced intracellular accumulation of topotecan, a known substrate for BCRP. Conversely, a lipophilic 7-modified camptothecin analogue (ST1481) displayed a complete lack of cross-resistance in HT29/MIT cells, suggesting that the drug was not a substrate for BCRP because no defects in intracellular accumulation were found. This conclusion is consistent with the antitumor efficacy of ST1481 against a BCRP-expressing tumor. These results may have therapeutic implications because the antitumor efficacy of ST1481 is in part related to a good bioavailability after oral administration, and the drug is currently under Phase I clinical evaluation.
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PMID:A novel 7-modified camptothecin analog overcomes breast cancer resistance protein-associated resistance in a mitoxantrone-selected colon carcinoma cell line. 1150 48

Melatonin has been reported to attenuate the oxidative damage caused by doxorubicin on kidney, brain, heart and bone marrow, whereas the in vivo antitumor effects of doxorubicin were not attenuated. The effects of melatonin on doxorubicin cytotoxicity have, therefore, been examined on human normal mammary epithelium HBL-100, on mammary adenocarcinoma MCF-7, on colon carcinoma LoVo, and on mouse P388 leukemia cell lines, and on tumor cell sublines pleiotropically resistant to anthracyclines. Melatonin in the concentration range 10-2000 pg/mL causes an inhibition of the growth of the human cell lines examined which is not clearly dose-dependent and less than 25% when significant. Melatonin similarly causes minor effects on doxorubicin cytotoxicity either on the parental human cell lines or on their resistant sublines. On the contrary, 200-1000 pg/mL melatonin cause a significant and dose-dependent partial sensitization to doxorubicin of resistant P388 mouse leukemia (P388/ADR), which occurs also in vivo, as indicated by a significant increase in survival time of the hosts. Doxorubicin intracellular concentrations in P388/ADR cells are increased by melatonin, suggesting that melatonin might inhibit P-glycoprotein-mediated doxorubicin efflux from the cells. These results indicate that the use of melatonin in clinical cancer treatment should not pose the risk of an attenuation of the effectiveness of doxorubicin, and encourage the further examination of the possible reduction by melatonin of the host toxicity of antitumor chemotherapy.
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PMID:Effects of melatonin on doxorubicin cytotoxicity in sensitive and pleiotropically resistant tumor cells. 1158 54


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