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)

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

The multidrug resistance (MDR) phenotype, either intrinsic and/or acquired, is discussed in relation to several MDR-associated markers such as P-glycoprotein (P-gp) encoded by mdr1, multidrug-resistance-associated protein (MRP) encoded by MRP and lung-resistance-associated protein (LRP) encoded by LRP. Well-characterized in vitro models are required to elucidate the mechanisms of MDR. The aim of the present study is the establishment of a drug-resistant subline from human colorectal adenocarcinoma HCT-15 that intrinsically expresses moderate levels of P-gp, MRP and LRP. Three adriamycin-resistant sublines (HCT-15/ADM1, HCT-15/ADM2 and HCT-15/ADM2-2) were established by stepwise exposure in growth medium that was supplemented with 25-200 ng/ml adriamycin-resulting in a 2.2- to 7.8-fold increase in IC(50) values by using the XTT assay. They were cross-resistant to MDR-related drugs, epirubicin, mitoxantrone, vincristine, etoposide and taxol, but not the MDR-unrelated drug, mytomycin C. The resistance to adriamycin was confirmed in vivo by a lack of sensitivity in athymic nude mice. Gene expression data for mdr1/P-gp, MRP/MRP and LRP/LRP on both mRNA and protein levels demonstrated that the molecules contributing to MDR in resistant sublines are mainly P-gp and partially MRP. The newly established adriamycin-resistant sublines of HCT-15 will provide clinically relevant tools to investigate how to overcome drug resistance and elucidate possible mechanisms of acquired MDR in human colon cancer.
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PMID:Establishment and characterization of adriamycin-resistant human colorectal adenocarcinoma HCT-15 cell lines with multidrug resistance. 1159 59

The expression levels of mRNAs for MDR1 (P-glycoprotein), multidrug resistance-associated proteins (MRP1, MRP2), and cytochrome P450 3A (CYP3A) in Caco-2 cells were quantitatively compared with those in human duodenal enterocytes, normal colorectal tissues, and colorectal adenocarcinomas. Caco-2 cells (passages 36-88) were kindly supplied by several laboratories in Japan. Human duodenal enterocytes were obtained from five healthy male volunteers. Normal colorectal tissues and colorectal adenocarcinomas were simultaneously obtained from seven patients with primary colorectal adenocarcinoma. MDR1, MRP1, MRP2, and CYP3A mRNA levels were determined by real-time quantitative polymerase chain reactions (PCR). Relative concentrations of mRNAs for target proteins (MDR1, MRP1, MRP2, and CYP3A) and glyceraldehyde-3-phosphate dehydrogenase in Caco-2 cells were 1.00 +/- 0.15, 1.02 +/- 0.06, 0.94 +/- 0.10, and 0.68 +/-0.60, respectively, and those in human enterocytes were about 12-, 3-, 7-, and 8000-fold higher than in the Caco-2 cells, respectively. In contrast, MDR1, MRP1, and CYP3A mRNA levels in Caco-2 cells were comparable to those in normal colorectal tissue and colorectal adenocarcinoma.
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PMID:Real-time quantitative polymerase chain reaction for MDR1, MRP1, MRP2, and CYP3A-mRNA levels in Caco-2 cell lines, human duodenal enterocytes, normal colorectal tissues, and colorectal adenocarcinomas. 1174 4

The permeability of 19 compounds in both the Caco-2/TC7 and HT29-MTX models was determined, and the ability of each model to predict intestinal absorption in humans was compared. Similar apparent permeability values (log P(app)) were obtained in both models for the majority of compounds tested, and plots of log P(app) versus fraction absorbed in humans gave comparable sigmoidal curves. A linear correlation was also observed between the log P(app) values derived from these two models, which suggests that HT29-MTX is an alternative model for absorption prediction in humans. The similarity of both the diffusion coefficients and permeability values obtained for a range of hydrophilic and lipophilic compounds in the two models indicates that the mucus layer secreted by the human adenocarcinoma HT29-MTX goblet cells does not constitute a diffusion barrier to such compounds. The lack of P-glycoprotein (P-gp) in the HT29-MTX cell line may explain the higher permeability values obtained for cimetidine and sumatriptan in this model compared with those derived from the Caco-2/TC7 monolayers. The results suggest that the HT29-MTX model can be used to rank order the passive permeability of compounds, irrespective of their potential interaction with P-gp, which may facilitate optimization of the physicochemical features of compounds within a chemical series.
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PMID:HT29-MTX and Caco-2/TC7 monolayers as predictive models for human intestinal absorption: role of the mucus layer. 1174 19

Nine tropane alkaloid aromatic esters (1-9) were isolated from the roots of Erythroxylum pervillei by following their potential to reverse multidrug-resistance with vinblastine-resistant oral epidermoid carcinoma (KB-V1) cells. All isolates, including seven new structures (3-9), were evaluated against a panel of human cancer cell lines, and it was found that alkaloids 3 and 5-9 showed the greatest activity with KB-V1 cells assessed in the presence of vinblastine, suggesting that these new compounds are potent modulators of P-glycoprotein. Confirmatory results were obtained with human ovarian adenocarcinoma (SKVLB) cells evaluated in the presence of adriamycin and synergistic studies performed with several cell lines from the NCI tumor panel. The structures of the new compounds were determined using spectroscopic techniques. Single-crystal X-ray analysis was performed on the monoester, tropane-3 alpha,6 beta,7 beta-triol 3-phenylacetate (1).
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PMID:Modulation of the multidrug-resistance phenotype by new tropane alkaloid aromatic esters from Erythroxylum pervillei. 1175 2

Chemotherapy-induced cell death is linked to apoptosis, and there is increasing evidence that multidrug-resistance in cancer cells may be the result of a decrease in the ability of a cell to initiate apoptosis in response to cytotoxic agents. In previous studies, we synthesized two classes of electrophilic tocopheryl quinones (TQ), nonarylating alpha-TQ and arylating gamma- and delta-TQ, and found that gamma- and delta-TQ, but not alpha-TQ, were highly cytotoxic in human acute lymphoblastic leukemia cells (CEM) and multidrug-resistant (MDR) CEM/VLB100. We have now extended these studies on tumor biology with CEM, HL60 and MDR HL60/MX2 human promyelocytic leukemia, U937 human monocytic leukemia, and ZR-75-1 breast adenocarcinoma cells. gamma-TQ, but not alpha-TQ or tocopherols, showed concentration and incubation time-dependent effects on loss of plasma membrane integrity, diminished viable cell number, and stimulation of apoptosis. Its cytotoxicity exceeded that of doxorubicin in HL60/MX2 cells, which express MRP, an MDR-associated protein. Apoptosis was confirmed by TEM, TUNEL, and DNA gel electrophoresis. Kinetic studies showed that an induction period was required to initiate an irreversible multiphase process. Gamma-TQ released mitochondrial cytochrome c to the cytosol, induced the cleavage of poly(ADP-ribose)polymerase, and depleted intracellular glutathione. Unlike xenobiotic electrophiles, gamma-TQ is a highly cytotoxic arylating electrophile that stimulates apoptosis in several cancer cell lines including cells that express MDR through both P-glycoprotein and MRP-associated proteins. The biological properties of arylating TQ electrophiles are closely associated with cytotoxicity and may contribute to other biological effects of these highly active agents.
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PMID:Gamma-tocopheryl quinone stimulates apoptosis in drug-sensitive and multidrug-resistant cancer cells. 1190 9

The multidrug-resistance (MR) status of camptothecin (CPT) was investigated in colon adenocarcinoma HT29 cells, leukemia K562, and breast carcinoma MCF7 cells expressing P-glycoprotein (Pgp) and/or MR-associated protein (MRP1). The concentration that induced 50% growth inhibition (IC(50)) against CPT was 0.14 and 0.20 microM in parental K562/WT and MCF7/WT cells, respectively. The drug resistant subline KH30 and MCF7/VP cells, which both overexpress MRP1, presented IC(50) values of 0.63 and 3.10 microM, respectively. The resulting resistance indexes were 3.80 and 12.50, respectively. However, in KH300 cells, a cell line that preferentially overexpresses Pgp, the IC(50) of CPT was 0.08 microM and thus did not exhibit resistance against CPT. In MCF7/DoX cells, preferentially overexpressing Pgp, but also a significant level of MRP1, the IC(50) of CPT was 0.64 microM and thus presented a resistance index of 3.26 against CPT. The cytotoxic effect of CPT was modulated in cells expressing MRP1 (MCF7/VP, HT29 cells) by the specific MRP1 modulators, probenecid and MK571. These results led us to consider CPT as a substrate for MRP1 and a potential modulator of MRP1 activity. To test this hypothesis, we examined the ability of nontoxic concentrations of CPT to sensitize MRP1-overexpressing cells to daunorubicin (DNR). In MCF7/VP and KH30 cells, nontoxic concentrations of CPT were able to enhance cytotoxicity of DNR and its nuclear accumulation. Sequential and simultaneous associations of CPT (100 nM) and DNR provided complete reversal of resistance, thus showing a synergistic effect in KH30 cells. However, simultaneous association (with 10 or 20 nM CPT) had an additive effect in MCF7/VP. These data suggest that CPT could be proposed as a candidate for the reversal of the MRP1 phenotype at clinically achievable concentrations.
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PMID:Reversal of multidrug resistance-associated protein-mediated daunorubicin resistance by camptothecin. 1211 4

Functional activity of multidrug resistance (MDR) markers (total activity of ABC-transporters, P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP) activities) in human colon adenocarcinoma and normal mucosa was examined. Functional activity of ABC-transporters was revealed in all colon tumors and in 70% of normal mucosa samples investigated. Expression of Pgp and MRP functional activity was determined in about 50% and 70% of colon tumors respectively. Pgp+MRP+ phenotype was determined in 36% of normal mucosa and adenocarcinoma samples. Expression of Pgp+MRP- phenotype was practically the same in normal mucosa and tumors (in 10 and 18% of samples respectively). Pgp-MRP+ phenotype was revealed two times more often in tumors than in mucosa--in 36 and 18% respectively. On the contrary, Pgp-MRP- phenotype was detected more rarely in tumors than in mucosa (in 10 and 36% of samples respectively). Transporters different from Pgp and MRP were also determined in some tumors and normal mucosa. At the patients with expression of Pgp function in normal mucosa the activity of the transporter was revealed in 25% of tumor samples only. On the contrary, at the patients with expression of MRP function in normal mucosa the activity of the transporter was revealed in 70% of tumor samples. At the patients with no expression of Pgp or MRP activity in normal mucosa the function of the transporters in tumors was determined in 60% and 70% of samples respectively. It is concluded that functional activity of various ABC-transporters (Pgp, MRP and other different from Pgp and MRP) is expressed in human colon adenocarcinoma; expression of ABC-transporters functional activity in normal mucosa does not predict MDR phenotype of the tumor.
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PMID:[Functional activity of ABC transporters (markers of multidrug resistance) in human colon adenocarcinoma and normal colonic mucosa]. 1251 89

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

A steroid xenobiotic receptor (SXR) is involved in the induction of MDR1/P-glycoprotein. MDR1 up-regulation by digoxin was previously demonstrated in human colon adenocarcinoma Caco-2 cells, but the participation of SXR remains unclear. Herein, the participation of SXR in MDR1 up-regulation was examined using reverse transcription-polymerase chain reaction in Caco-2 cells, and digoxin-tolerant cells (Caco/DX) as well as human colon carcinoma LS180 cells, which expressed SXR. MDR1 mRNA expression in Caco-2 or LS180 cells was increased by exposure to 1 microM digoxin for 24h, in a concentration-dependent manner, but SXR mRNA decreased concentration-dependently and was undetectable or significantly lower at 1 microM digoxin, indicating antithetical changes in MDR1 and SXR mRNA expression. Moreover, the MDR1 mRNA level was higher in Caco/DX cells than Caco-2 cells, whereas the SXR mRNA level was lower in Caco/DX cells. Consequently, digoxin was demonstrated to up-regulate MDR1 mRNA and simultaneously down-regulate SXR mRNA expression.
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PMID:Digoxin up-regulates multidrug resistance transporter (MDR1) mRNA and simultaneously down-regulates steroid xenobiotic receptor mRNA. 1462 6


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