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 aim of this work was to determine the expression of the multidrug resistance (MDR) proteins, namely MDR1 (P-glycoprotein), MRP1 (multidrug resistance-related protein) and LRP (lung resistance-related protein), in 87 samples of breast carcinoma. Detection of these proteins was provided by using indirect enzymatic immunohistochemistry. Our findings were compared with the other clinical and pathological parameters: expression of Her2/neu, estrogen receptor status (ER), progesteron receptor status (PR), histological grade and regional lymph node status. For statistical analysis, non-parametric two sided Mann-Whitney-U test was used. Majority of breast carcinoma specimens show positivity for these proteins. The MDR1 and MRP1 signal was found in the cytoplasm of cancer cells. The expression of LRP was detected in the cytoplasm close to the nuclear membrane. The samples were positive for MDR1 protein in 57%, for MRP1 in 84% and for LRP in 79%. Comparing our results with other clinical and pathological parameters, negative correlation between ER, PR and MDR1 expressions and histological grading status was found. No associations were observed between the MRP1 and LRP proteins and histological grading, as well as between the expression of three MDR proteins and the other clinically relevant parameters. In conclusion, high frequency of expression of MDR proteins in breast carcinoma cells suggests, that these proteins might be an important factor of drug resistance in breast carcinoma. Nevertheless, the negative correlation between the histological grade of malignancy of tumor and the expression of ER, PR and MDR1 indicates possible influence of progressive tumor cell de-differentiation. However, this finding has to be confirmed in additional evaluations.
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PMID:Expression of MDR proteins in breast cancer and its correlation with some clinical and pathological parameters. 1657 68

Transmembrane transport of endogenous as well as synthetic opioid peptides is a critical determinant of pharmacokinetics and biologic efficacy of these peptides. This transport process influences the distribution of opioid peptides across the blood-brain barrier and their elimination from the body. A multitude of transport systems that recognize opioid peptides as substrates have been characterized at the functional level, and these transport systems are expressed differentially at different sites in the body. Many of these transport systems have been identified at the molecular level. These include the H(+)-coupled peptide transporters PEPT1 and PEPT2, the adenosine triphosphate-dependent efflux transporters P-glycoprotein and multidrug resistance-related protein 2, and several members of the organic anion-transporting polypeptide gene family. There are however many additional transport systems that are known to transport opioid peptides but their molecular identities still remain unknown.
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PMID:Transport systems for opioid peptides in mammalian tissues. 1659 37

Interindividual differences of drug response are an important cause of treatment failures and adverse drug reactions. The identification of polymorphisms explaining distinct phenotypes of drug metabolizing enzymes contributed in part to the understanding of individual variations of drug plasma levels. However, bioavailability also depends on a major extent from the expression and activity of drug transport across biomembranes. In particular efflux transporters of the ATP-binding cassette (ABC) family such as ABCB1 (P-glycoprotein, P-gp), the ABCC (multidrug resistance-related protein, MRP) family and ABCG2 (breast cancer resistance protein, BCRP) have been identified as major determinants of chemoresistance in tumor cells. They are expressed in the apical membranes of many barrier tissue such as the intestine, liver, blood-brain barrier, kidney, placenta, testis and in lymphocytes, thus contributing to plasma, liquor, but also intracellular drug disposition. Since expression and function exhibit a broad variability, it was hypothesized that hereditary variances in the genes of membrane transporters could explain at least in part interindividual differences of pharmacokinetics and clinical outcome of a variety of drugs. This review focuses on the functional significance of single nucleotide polymorphisms (SNP) of ABCB1, ABCC1, ABCC2, and ABCG2 in in vitro systems, in vivo tissues and drug disposition, as well as on the clinical outcome of major indications.
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PMID:Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs. 1676 35

Anthracyline antibiotics, produced by Streptomyces sp., still rank among the most efficient anticancer drugs in clinical use. Aim of this study was to gain deeper insight into the anticancer properties of the anthracycline-related angucycline landomycin E (LE). The impact of LE on nuclear morphology was assessed by 4',6-diamidino-2-phenylindole (DAPI) staining in the human carcinoma cell model KB-3-1. LE treatment led to the appearance of typical morphological signs of programmed cell death like cell shrinkage, chromatin condensation and formation of apoptotic bodies. Apoptotic cell death induced by LE was further characterised by caspase (substrate) cleavage and intense mitochondrial membrane depolarisation (JC-1 and rhodamine 123 staining) already after 1h drug incubation. Moreover, incubation with LE led to reduced intracellular ATP pools suggesting LE-induced apoptotic cell death as a consequence of rapid mitochondrial damage. Furthermore, LE treatment led to profound generation of intracellular oxidative stress, indicated by radical scavenger pre-treatment and dichlorofluorescin diacetate (DCF-DA) staining experiments. Since chemoresistance is a common problem in cancer therapy, we also investigated the influence of ABCB1 (P-glycoprotein, P-gp), ABCC1 (multidrug resistance-related protein, MRP1) and ABCG2 (breast cancer resistance protein, BCRP) overexpression on the anticancer activity of LE. Compared to anthracyclines, cytotoxic activity of LE was only weakly reduced by P-gp and MRP1 overexpression. Moreover, BCRP expression had no influence on LE anticancer activity. In summary, LE exerts anticancer activity via potent induction of apoptosis and has promising anticancer activity even against multidrug resistant (MDR) cells. Taken together, these data suggest further development of LE as a new anticancer drug.
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PMID:Mechanisms underlying the anticancer activities of the angucycline landomycin E. 1790 9

beta-caryophyllene is a sesquiterpene widely distributed in essential oils of various plants. Several biological activities are attributed to beta-caryophyllene, such as anti-inflammatory, antibiotic, antioxidant, anticarcinogenic and local anaesthetic activities. In this work, the potentiating effect of beta-caryophyllene on the anticancer activity of alpha-humulene, isocaryophyllene and paclitaxel against MCF-7, DLD-1 and L-929 human tumour cell lines was evaluated. A non-cytotoxic concentration of beta-caryophyllene significantly increased the anticancer activity of alpha-humulene and isocaryophyllene on MCF-7 cells: alpha-humulene or isocaryophyllene alone (32 microg mL(-1)) inhibited cell growth by about 50% and 69%, respectively, compared with 75% and 90% when combined with 10 microg mL(-1) beta-caryophyllene. Moreover, beta-caryophyllene potentiated the anticancer activity of paclitaxel on MCF-7, DLD-1 and L-929 cell lines. The highest potentiating effect was obtained in DLD-1 cells treated with paclitaxel combined with 10 microg mL(-1) beta-caryophyllene, which increased the paclitaxel activity about 10-fold. The intracellular accumulation of paclitaxel-oregon green was evaluated in combination with concentrations of beta-caryophyllene ranging from 2.5 to 40 microg mL(-1). beta-Caryophyllene (10 microg mL(-1)) significantly increased the intracellular accumulation of paclitaxel-oregon green (about 64% over controls). Moreover, beta-caryophyllene induced intracellular accumulation of calcein but not verapamil, an inhibitor of P-glycoprotein and multidrug resistance related protein transporters, suggesting that beta-caryophyllene promotes drug accumulation by a different mechanism of action. These results suggest that beta-caryophyllene facilitates the passage of paclitaxel through the membrane and thus potentiates its anticancer activity.
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PMID:Potentiating effect of beta-caryophyllene on anticancer activity of alpha-humulene, isocaryophyllene and paclitaxel. 1805 25

The ATP-binding cassette (ABC) transporter ABCC1, or multidrug resistance-related protein 1 (MRP1) is implicated in Phase II metabolism and multidrug resistance as it effluxes substrate anticancer drugs. As cannabinoids inhibit two related ABC transporters, P-glycoprotein and ABCG2, here we examined whether they also inhibit ABCC1. Indeed, the cannabinoids enhanced the intracellular accumulation of two ABCC1 substrates, Fluo3 and vincristine, in ovarian carcinoma cells over-expressing ABCC1 (2008/MRP1) with a rank order of potency: cannabidiol>cannabinol>Delta(9)-tetrahydrocannabinol. Cannabinoid inhibition of ABCC1 was confirmed using insect cell membrane MRP1 ATPase assays. These results demonstrate that cannabinoids inhibit ABCC1.
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PMID:Interaction of plant cannabinoids with the multidrug transporter ABCC1 (MRP1). 1861 55

Human mutant-type (mt) p53 cDNA was synthesized and cloned from human lung cancer cell line GL containing mt-p53 gene by using polymerase chain reaction (PCR). It was confirmed that the mt-p53 cDNA contained the complete coding sequence of p53 gene but mutated at codon 245 (G-->T) and resulted in glycine to cysteine by sequencing analysis. The retroviral vector pD53M of the mt-p53 was constructed and introduced into the drug-sensitive human lung cancer cells GAO in which p53 gene did not mutate. The transfected GAO cells strongly expressed mutant-type p53 protein by immunohistochemistry, showing that pD53M vector could steadily express in GAO cells. The drug resistance to several anticancer agents of GAO cells infected by pD53M increased in varying degrees, with the highest increase of 4-fold,in vitro andin vivo. By quantitative PCR and flow cytometry (FCM) analyses, the expression of MDR1 gene and the activity of P-glycoprotein (Pgp) did not increase, the expression of MRP gene and the activity of multidrug resistance-related protein (Mrp) increased slightly. These results indicated that the drug resistance associated with mt-p53 gene might be somewhat correlated with MRP/Mrp but not with MDR1/Pgp. It was possible to modify the tumor drug resistance by changing status of p53 gene.
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PMID:Increasing drug resistance in human lung cancer cells by mutant-type p53 gene mediated by retrovirus. 1872 4

Multidrug resistance in gliomas is the major challenges in the clinical setting. We investigated the expression of P-glycoprotein (Pgp) and multidrug resistance-related protein 1 (MRP1) in 50 gliomas using immunohistochemistry. Compared to Pgp, MRP1 positivity was observed in highest percentage of gliomas grade IV samples (p = 0.008). Unlike MRP1 expression observed in high-grade, gliomas grade II exhibited a greater number of Pgp positive samples as compared to grades III and IV (p = 0.026). Our results suggest that the difference between the histological grade gliomas regarding MRP1 and Pgp expression must have implications in the choice of chemotherapeutic protocols.
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PMID:Differences in the expression pattern of P-glycoprotein and MRP1 in low-grade and high-grade gliomas. 1879 65

Moxifloxacin (MXF) is a fluoroquinolone antibiotic that is effective against respiratory infections. However, the mechanisms of MXF lung diffusion are unknown. Active transport in other tissues has been suggested for several members of the fluoroquinolone family. In this study, transport of MXF was systematically investigated across a Calu-3 lung epithelial cell model. MXF showed polarized transport, with the secretory permeability being twice as high as the absorptive permeability. The secretory permeability was concentration dependent (apparent P(max) = 13.6 x 10(-6) cm x s(-1); apparent K(m) = 147 microM), suggesting saturated transport at concentrations higher than 350 microg/ml. The P-glycoprotein inhibitor PSC-833 inhibited MXF transport in both directions, whereas probenecid, a multidrug resistance-related protein inhibitor, appeared to have no effect in the Calu-3 model. Moreover, rifampin, a known inducer of efflux transport proteins, upregulated the expression of P-glycoprotein in Calu-3 cells and enhanced MXF active transport. In conclusion, this study clearly indicates that MXF is subject to P-glycoprotein-mediated active transport in the Calu-3 model. This P-glycoprotein-dependent secretion may lead to higher MXF epithelial lining fluid concentrations than those in plasma. Furthermore, drug-drug interactions may be expected when MXF is combined with other P-glycoprotein substrates or modulators.
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PMID:P-glycoprotein-mediated transport of moxifloxacin in a Calu-3 lung epithelial cell model. 1918 90

Glucocorticoids are often used in veterinary cancer patients because of their anti-inflammatory actions, appetite-stimulating effects, ability to decrease nausea and vomiting associated with some chemotherapy agents, and, in some instances, for their cytotoxic actions on susceptible tumour cells. Veterinary oncologists may not consider the possibility that the use of glucocorticoids may adversely affect response to chemotherapy. There is evidence that glucocorticoids can up-regulate the expression of multidrug resistance genes in some tissues. Whether or not glucocorticoid-induced expression of multidrug resistance proteins occurs in tumour cells is not presently known. The purpose of this study was to determine if dexamethasone induces P-glycoprotein (P-gp) or multidrug resistance-related protein 1 (MRP1) in tumour cell lines. A canine osteosarcoma cell line (OS2.4) and a human myeloid leukaemia cell line 60 (HL60) were treated in culture with dexamethasone. The presence of a glucocorticoid receptor was confirmed in both cell lines by reverse-transcriptase polymerase chain reaction. Western blots for P-gp and MRP1 expression were performed on vehicle-treated and dexamethasone-treated cells. Sensitivity towards several chemotherapeutic drugs (cisplatin (cis-diamminedichloroplatinum), doxorubicin, methotrexate and vincristine) was determined by 3-(4,5-dimthylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. While dexamethasone treatment of OS2.4 cells increased the resistance to cisplatin and methotrexate, an increase in P-gp or MRP1 expression was not observed. Dexamethasone-treated HL60 cells did not develop chemoresistance and did not show increased expression of P-gp or MRP1.
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PMID:Dexamethasone treatment of a canine, but not human, tumour cell line increases chemoresistance independent of P-glycoprotein and multidrug resistance-related protein expression. 1937 18


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