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)

Protease inhibitors are very effective in treating patients infected with HIV. However, many drugs in this class penetrate poorly into the central nervous system (CNS) and may permit this site to be a sanctuary from which resistant virus can emerge. Previous studies have shown that the protease inhibitor saquinavir (SQV) interacts with the multidrug transport system, P-glycoprotein (P-gp), expressed in epithelial cells in the gut mucosa and at the blood-brain barrier, and thus might affect both the oral absorption and the penetration of SQV into the CNS. To determine whether SQV is a substrate for P-gp, its uptake was determined in cancer cells, which do (Dx5) and do not (MES-SA) express P-gp. The distribution of SQV between brain tissue and plasma was also investigated in rats and in normal and P-gp-deficient mdr1a(-/-) mice. The distribution ratio of SQV in plasma:brain:cerebrospinal fluid was approximately 100:10:0.2 in rats. The accumulation of SQV was enhanced in MES-SA cells (P-gp-negative) versus Dx5 cells (P-gp-positive). Bolus i.v. injection of [(14)C]SQV (2 and 5 mg/kg) into mdr1a(-/-) and normal mice (n = 3 or 4) resulted in 3-fold higher radioactivity in brains from mdr1a(-/-) mice. Similarly, oral administration of [(14)C]SQV (500 mg/kg) resulted in a 5-fold increase in systemic exposure and a 10-fold increase in brain levels in mdr1a(-/-) mice. These data demonstrate that saquinavir is a substrate for P-gp and that this transport system may play a role in limiting oral absorption and CNS exposure to this protease inhibitor.
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PMID:The disposition of saquinavir in normal and P-glycoprotein deficient mice, rats, and in cultured cells. 1095 Aug 49

Single-step selection with vinblastine was performed in populations of the human sarcoma cell line MES-SA, to assess cellular mechanisms of resistance to the drug and mutation rates via fluctuation analysis. At a stringent selection with 20 nM vinblastine, resulting in 5-6 logs of cell killing, the mutation rate was 7 x 10(-7)per cell generation. Analysis of variance supported the hypothesis of spontaneous mutations conferring vinblastine resistance, rather than induction of adaptive response elements. Surviving clones displayed a stable multidrug resistance phenotype over a 3-month period. All propagated clones demonstrated high levels of resistance to vinblastine and paclitaxel, and lower cross-resistance to doxorubicin and etoposide. Activation of MDR 1 gene expression and P-glycoprotein function was demonstrable in all clones. No elevation was found in the expression of the mrp gene, the LRP-56 major vault protein and beta-tubulin isotypes (M40, beta4, 5beta, and beta9) in these mutants. We conclude that initial-step resistant mechanism in these vinblastine-selected mutants commonly arises from a stochastic mutation event with activation of the MDR 1 gene.
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PMID:MDR 1 activation is the predominant resistance mechanism selected by vinblastine in MES-SA cells. 1097 Jun 91

Activation of the MDR1 (ABCB1) gene is a common event conferring multidrug resistance (MDR) in human cancers. We investigated MDR1 activation in MDR variants of a human sarcoma line, some of which express a mutant MDR1, which facilitated the study of allelic gene expression. Structural alterations of MDR1, gene copy numbers, and allelic expression were analyzed by cytogenetic karyotyping, oligonucleotide hybridization, Southern blotting, polymerase chain reaction, and DNA heteroduplex assays. Both chromosome 7 alterations and several cytogenetic changes involving the 7q21 locus are associated with the development of MDR in these sarcoma cells. Multistep-selected cells and their revertants contain three- to six-fold MDR1 gene amplification compared with that of the drug-sensitive parental cell line MES-SA and single-step doxorubicin-selected mutants. MDR1 gene amplification precedes the emergence of a mutant allele in cells that were coselected with doxorubicin and a cyclosporin inhibitor of P-glycoprotein (P-gp). Allele-specific oligonucleotide hybridization showed that the endogenous mutant allele was present as a single copy, with multiple copies of the normal allele. Reselection of revertant cells with doxorubicin in either the presence or the absence of the P-gp inhibitor resulted in exclusive reexpression of the mutant MDR1 allele, regardless of the presence of multiple wild-type MDR1 alleles. These data provide new insights into how multiple alleles are regulated in the amplicon of drug-resistant cancer cells and indicate that increased expression of an amplified gene can result from selective transcription of a single mutant allele of the gene.
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PMID:Preferential expression of a mutant allele of the amplified MDR1 (ABCB1) gene in drug-resistant variants of a human sarcoma. 1211 26

Although the coincidental amplification and accompanying overexpression of bystander genes that neighbor oncogene targets occur frequently during the development of human tumors, little has been done to investigate the functional or biological consequences of amplified bystander gene overexpression. LANCL2 (LANC-like 2) is a bystander gene that is coamplified and overexpressed with epidermal growth factor receptor in approximately 20% of all glioblastomas. This gene has also been designated as Testis Adriamycin Sensitivity Protein because it is most highly expressed in testis and its expression has been noted to increase cellular sensitivity to Adriamycin. Because of the latter association, we have examined potential relationships between LANCL2 and the expression of multidrug-resistance (MDR)1, as well as its cognate protein, P-glycoprotein (P-gp), because elevated expression of P-gp is known to increase cell resistance to many cytotoxic drugs, including Adriamycin. Using the Dx5 derivative of MES-SA cells in which P-gp is overexpressed, we show that the level of endogenous P-gp decreases with increased expression of exogenous LanCl-2 and that cells with reduced P-gp show increased sensitivity to Adriamycin. Results from reverse transcription-PCR and MDR1 promoter activity analyses suggest that LanCl-2 transcriptionally suppresses MDR1, and this interpretation of LanCl-2 function is consistent with results from immunofluorescence analysis, which shows that LanCl-2 resides in the nucleus, as well as at the plasma membrane. With respect to this study, our data indicate that LanCl-2 increases cellular sensitivity to Adriamycin by decreasing the expression of P-gp, but more generally, these results indicate that the identification of bystander gene amplification in human tumors can have clinical implications.
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PMID:Lanthionine synthetase components C-like 2 increases cellular sensitivity to adriamycin by decreasing the expression of P-glycoprotein through a transcription-mediated mechanism. 1256 19

The present study was performed to compare the cardiovascular adverse effects of verapamil, KR30031 and their optical isomers, and also to measure their ability to overcome multidrug resistance (MDR). The R-isomer of KR30031 (R-KR30031) was equipotent with the S-isomer of KR30031 (S-KR30031) and 25-fold less potent than the R-isomer of verapamil (R-verapamil) in relaxing the aorta isolated from rat (EC50: 11.8, 10.2 and 0.46 microM, respectively). The effect of R-KR30031 in decreasing left ventricular pressure of heart isolated from rat was 2- and 267-fold smaller than those of S-KR30031 and R-verapamil, respectively (EC50: 23.9, 9.4 and 0.089 mM, respectively). The hypotensive effect of R-KR30031 in rat was about 2- and 23-fold smaller than those of S-KR30031 and R-verapamil, respectively (ED20: 1.15, 0.60 and 0.05 mg/kg, respectively). On the other hand, R-KR30031 elicited potency similar to those of S-KR30031 and R-verapamil in enhancing the paclitaxel-induced cytotoxicity to HCT15/CL02 and MES-SA/DX5 cells that reveal high levels of P-glycoprotein expression (IC50: 3.11, 3.04 and 2.58 microM, respectively). In addition, the intrinsic cytotoxicity of R-KR30031 in HCT15/CL02 and MES-SA/DX5 cells was observed only at the very high concentration of 100 microM. All these results suggest that R- and racemic KR30031 are active modulators of MDR with potentially minimal cardiovascular adverse activity.
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PMID:Differential effects of the optical isomers of KR30031 on cardiotoxicity and on multidrug resistance reversal activity. 1256 5

Idarubicin (IDA) is an anthracycline anticancer drug utilized in the treatment of acute leukemias. There are conflicting data published with regard to the cross-resistance of IDA in multidrug-resistant (MDR) cells expressing P-glycoprotein (P-gp). We evaluated the cytotoxicity and cellular accumulation of IDA in a panel of anthracycline-selected MDR cell lines. Leukemia K562/R7 cells and sarcoma MES-SA/Dx5 cells expressing high levels of the MDR1 (ABCB1) gene were resistant to IDA (42-fold and 150-fold, respectively). In both of these cell lines, resistance to IDA was equivalent to that for doxorubicin, the drug used to select for the MDR variants. The P-gp inhibitor PSC 833 (valspodar) at 2 microM completely restored sensitivity to IDA. IDA accumulation was decreased 12-fold in MES-SA/Dx5 cells vs parental cell line, and drug uptake was restored to control levels by PSC 833. Reduced intracellular IDA was correlated with P-gp content by flow cytometry. Experiments in NIH3T3 murine cells transfected with the human MDR1 gene substantiated the findings of cross-resistance to IDA and reversal of resistance by PSC 833. Our data indicate that IDA is a high-affinity substrate for P-gp.
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PMID:Modulation of resistance to idarubicin by the cyclosporin PSC 833 (valspodar) in multidrug-resistant cells. 1464 19

The multidrug-resistant cancer cell lines NCI/AdR(RES) and MES-SA/DX-5 have higher glycolipid levels and higher P-glycoprotein expression than the chemosensitive cell lines MCF7-wt and MES-SA. Inhibiting glycolipid biosynthesis by blocking glucosylceramide synthase has been proposed to reverse drug resistance in MDR cells by causing an increased accumulation of proapoptotic ceramide during treatment of cells with cytotoxic drugs. We treated both multidrug-resistant cell lines with the glucosylceramide synthase inhibitors PDMP (d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol), C9DGJ (N-nonyl-deoxygalactonojirimycin) or C4DGJ (N-butyl-deoxygalactonojirimycin). PDMP achieved a significant reversal of drug resistance in agreement with previous reports. However, the N-alkylated iminosugars C9DGJ and C4DGJ, which are more selective glucosylceramide synthase inhibitors than PDMP, failed to cause any reversal of drug resistance despite depleting glycolipids to the same extent as PDMP. Our results suggest that (a) inhibition of glucosylceramide synthase does not reverse multidrug resistance and (b) the chemosensitization achieved by PDMP cannot be caused by inhibition of glucosylceramide synthase alone.
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PMID:Inhibition of glucosylceramide synthase does not reverse drug resistance in cancer cells. 1526 8

The choice of cell lines for multidrug resistance (MDR) modulators screening may affect the results obtained. Screening is most often performed in model systems which employ cell lines derived from haematological malignancies. Cell lines originating from solid tumours are far less popular. In the present work, we aimed to test the usefulness of the drug-sensitive human sarcoma cell line MES-SA, and its multidrug-resistant counterpart MES-SA/Dx5, as a model system for modulators' anti-MDR potency evaluation. Overexpression of P-glycoprotein in the resistant but not in the sensitive cell line was confirmed by flow cytometry and confocal microscopy. Flow cytometry demonstrated that verapamil and trifluoperazine reduced MDR in MES-SA/Dx5 cells as assessed by the rhodamine 123 accumulation test. Both modulators also restored in MES-SA/Dx5 cells the drug accumulation pattern typical for sensitive cells, as judged by confocal microscopy. We conclude that the MES-SA and MES-SA/Dx5 cell line pair constitute a good model for MDR modulators study.
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PMID:Human sarcoma cell lines MES-SA and MES-SA/Dx5 as a model for multidrug resistance modulators screening. 1581 62

Drug resistance is a major problem for chemotherapy. Entrapment of anticancer drugs in endolysosomal compartments or active extrusions by plasma membrane proteins of the ATP-binding cassette (ABC) superfamily are important resistance mechanisms. This study evaluated photochemical internalization (PCI) of membrane-impermeable macromolecules that are not the target of ABC drug pumps for treating multidrug-resistant (MDR) cancer cells. We used the drug-sensitive uterine fibrosarcoma cell line MES-SA and its MDR, P-glycoprotein (P-gp)-overexpressing derivative MES-SA/Dx5 with the photosensitizer disulfonated meso-tetraphenylporphine (TPPS(2a)) and broad spectrum illumination. The PCI of doxorubicin, the ribosome-inactivating protein gelonin and adenoviral transduction were assessed in both cell lines, together with the uptake and excretion of TPPS(2a) and of two fluid phase markers easily detectable by fluorescence [lucifer yellow (LY) and fluorescein isothiocyanate (FITC)-dextran], as a model of gelonin uptake. Both cell lines were resistant to PCI of doxorubicin, but equally sensitive to PCI of gelonin, even though the endocytosis rates of LY and FITC-dextran were significantly lower in the MDR cells. In control studies, MES-SA/Dx5 cells were more resistant to photodynamic therapy (TPPS(2a) + light only). This was not mediated by P-gp, as there were no differences in the uptake and efflux of TPPS(2a) between the cell lines. After adenoviral infection, PCI enhanced gene delivery in both cell lines. In conclusion, PCI of macromolecular therapeutic agents that are not targets of P-gp is a novel therapeutic strategy to kill MDR cancer cells.
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PMID:Photochemical internalization of therapeutic macromolecular agents: a novel strategy to kill multidrug-resistant cancer cells. 1690 53

The ability of cancer cells to become simultaneously resistant to different drugs, a trait known as multidrug resistance, remains a major obstacle for successful anticancer therapy. One major mechanism of resistance involves cellular drug efflux by expression of P-glycoprotein (P-gp), a membrane transporter with a wide variety of substrates. Anthracyclines are especially prone to induction of resistance by the P-gp mechanism. P-gp mediated resistance is often confronted by use of P-gp inhibitors, synthesis of novel analogs, or conjugating drugs to macromolecular carriers in order to circumvent the efflux mechanism. In this report, the effect of free and Elastin-like polypeptide (ELP) bound doxorubicin (Dox) on the viability of sensitive (MES-SA and MCF-7) and multidrug resistant (MES-SA/Dx5 and NCI/ADR-RES) human carcinoma cells was studied in vitro. The resistant MES-SA/Dx5 cells demonstrated about 70 times higher resistance to free Dox than the sensitive MES-SA cells, and the NCI/ADR-RES cells were about 30 fold more resistant than the MCF-7 cells. However, the ELP-bound Dox was equally cytotoxic in both sensitive and resistant cell lines. The ELP-bound Dox was shown to accumulate in MES-SA/Dx5 cells, as opposed to free Dox, which was rapidly pumped out by the P-gp transporter. Since ELP is a thermally responsive carrier, the effect of hyperthermia on the cytotoxicity of the ELP-Dox conjugate was investigated. Both cytotoxicity and apoptosis were enhanced by hyperthermia in the Dox resistant cells. The results suggest that ELP-Dox conjugates may provide a means to thermally target solid tumors and to overcome drug resistance in cancer cells.
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PMID:A thermally targeted elastin-like polypeptide-doxorubicin conjugate overcomes drug resistance. 1748 74


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