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

---

Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study demonstrates that the flavonoid quercetin (Q), a plant-derived compound with low toxicity in vivo, greatly potentiates the growth-inhibitory activity of Adriamycin (ADR) on MCF-7 ADR-resistant human breast cancer cells. The effect of Q was dose-dependent at concentrations ranging between 1 and 10 microM. Since ADR resistance in these cells is associated with the expression of high levels of P-glycoprotein (Pgp), we evaluated the effect of Q and related flavonoids of Pgp activity in cytofluorographic efflux experiments with the fluorescent dye rhodamine 123 (Rh 123). Our results indicate that Q and 3-OMe Q (3',4',7-trimethoxyquercetin) but not the 3-rhamnosylglucoside of Q (rutin) inhibit the Pgp pump-efflux activity in a dose-related manner. Moreover, 10 microM Q reduces the expression of the immunoreactive Pgp in MCF-7 ADR-resistant cells as evaluated by cytofluorimetric assay. In conclusion, these findings provide a further biological basis for the potential therapeutic application of Q as an anti-cancer drug either alone or in combination with ADR in multidrug-resistant breast tumor cells.
...
PMID:Quercetin potentiates the effect of adriamycin in a multidrug-resistant MCF-7 human breast-cancer cell line: P-glycoprotein as a possible target. 763 87

To investigate the relationship between oncogene activation and appearance of multidrug resistance (MDR) we transfected the human breast epithelial cell line MCF-10A, negative for the expression of the P-glycoprotein, with c-Ha-ras and/or c-erbB-2 oncogenes. The appearance of the MDR phenotype was then studied by evaluating mdr-1 mRNA expression, the presence of P-glycoprotein on the cell membrane and the onset of doxorubicin resistance, together with the effect of the reversing agent verapamil. We found that only MCF-10A transfected with both c-Ha-ras and c-erbB-2 oncogenes acquired the MDR phenotype.
...
PMID:Induction of multidrug resistance (MDR) by transfection of MCF-10A cell line with c-Ha-ras and c-erbB-2 oncogenes. 792 21

Multidrug resistance (MDR) is the phenomenon in which cells become resistant to several classes of structurally and functionally diverse drugs after exposure to a single cytotoxic agent. One form of MDR is associated with the overexpression of a large plasma membrane phosphoglycoprotein, P-glycoprotein, which acts as an energy-requiring drug transport pump. Protein kinase C may participate in MDR through posttranslational modification of P-glycoprotein. The purpose of this study is to critically evaluate P-glycoprotein as a substrate for protein kinase C and to determine whether phosphorylation leads to changes in drug transport. Protein kinase C from rat brain phosphorylated immunoprecipitated P-glycoprotein in a manner dependent on the activation of the exogenous kinase. Phorbol 12-myristate 13-acetate (PMA) increased the phosphorylation of P-glycoprotein 6-fold and selectively decreased the accumulation of vinblastine in resistant MCF-7/AdrR cells. PMA selectively decreased the cellular association of vinblastine with MDR cells after brief periods of incubation, but only after critical concentrations of drug were achieved. The actions of PMA did not require new synthesis of P-glycoprotein. PMA had similar effects in MCF-7/BC-19, a cell line transfected with a cDNA for P-glycoprotein. Staurosporine inhibited the effects of PMA on the phosphorylation of P-glycoprotein and on the accumulation of vinblastine. These data demonstrated that immunoprecipitated P-glycoprotein can be a substrate for protein kinase C, and that phosphorylation of the transporter is associated with significant changes in drug transport.
...
PMID:Functional role of phosphorylation of the multidrug transporter (P-glycoprotein) by protein kinase C in multidrug-resistant MCF-7 cells. 794 66

The surface and intracellular expression of mdrI-P-glycoprotein in parental drug-sensitive human breast cancer cells (MCF-7) and their multidrug-resistant (MDR) variants has been studied by using the monoclonal antibodies (MAbs) MM4.17 and MRK-16, which recognize 2 different epitopes of the drug efflux pump molecule. Fluorescence microscopic observations showed that P-glycoprotein, in addition to being located at the cell surface, can also be found in the Golgi apparatus of resistant cells. To confirm this finding, Golgi apparatus and P-glycoprotein were double-labelled with wheat-germ agglutinin (WGA) and MAb MM4.17. Laser scanning confocal microscopy indicated that, in MDR cells, Adriamycin mainly accumulated cytoplasmically in a perinuclear region. This accumulation proved to be modulated by pre-treatment with verapamil or ATP depletion. Moreover, the vital staining of Adriamycin-treated MDR cells, performed with the fluorescent lipid N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]- 6-aminocaproyl sphingosine (C6-NBD-ceramide), revealed that the anthracyclinic antibiotic was located in the Golgi apparatus. All these results indicate that the drug transporter is located in the Golgi apparatus, in which Adriamycin molecules also accumulate.
...
PMID:P-glycoprotein expression in the Golgi apparatus of multidrug-resistant cells. 798 20

Multidrug resistance (MDR) corresponds to the cross-over resistance of tumour cells to structurally unrelated cytotoxic chemotherapeutic drugs. One of the mechanisms causing this resistance is the enhanced expression of a transmembrane drug efflux pump P-glycoprotein (P-170). Reversal of P-glycoprotein-associated MDR has received much attention in recent years. In experimental cell lines, P-170 and the glutathione redox cycle seem to contribute to this phenomenon; P-170 may be inactivated by calcium and calmodulin antagonists and the glutathione redox cycle altered by buthionine sulphoximine (BSO). Treatment of human MCF-7 breast cancer cells with chemosensitizers (CS), such as verapamil, trifluoperazine or BSO, for 72 hr resulted in an enhanced sensitization of cells to Adriamycin, trifluoperazine being the most potent compound in the reversion of chemoresistance. In these Adriamycin sensitive or resistant cells, treated or not by the CS, the possible role of calcium and cyclic adenosine monophosphate (cAMP) in mediating the reversion of chemoresistance to Adriamycin was investigated. It was found that intracellular calcium was approximately 2-fold higher in resistant than in sensitive cells, the opposite was true for cAMP. Modifications in calcium and cAMP levels were observed in MCF-7 resistant cells after treatment with verapamil and BSO; trifluoperazine had no effect on these two parameters. These results seemed to rule out any implication of calcium and cAMP levels in the contribution of these three chemosensitizers in the mechanisms of reversion of chemoresistance to Adriamycin.
...
PMID:Comparative study of intracellular calcium and adenosine 3',5'-cyclic monophosphate levels in human breast carcinoma cells sensitive or resistant to Adriamycin: contribution to reversion of chemoresistance. 808 Apr 43

The multidrug resistance (MDR) phenotype induces cross-resistance to many chemotherapeutic agents in cancer cells. Protein kinase C (PKC) has been implicated in the regulation of the MDR phenotype. In order to determine the role of specific PKC isoenzymes in regulating the MDR phenotype, the expression and activity of PKC isoenzymes in the human breast cancer cell line, MCF-7-WT, and an MDR subline, MCF-7-MDR, were examined. The MDR phenotype was associated with a 10-fold increase in calcium-dependent PKC activity as well as a 10-fold decrease in calcium-independent activity was due to a selective increase in the activity was due to a selective increase in the expression of PKC alpha as determined by Western blot analysis and hydroxylapatite chromatography. This increase in expression of PKC alpha was regulated at the message level as demonstrated by Northern blot analysis. The decrease in calcium-independent activity was caused by a decrease in the expression of PCK delta and epsilon. The significance of the increase in PKC alpha expression was then demonstrated by a commensurate 11-fold increase in the basal and stimulated phosphorylation of the myristolated alanine-rich C kinase substrate. Phosphorylation of P-glycoprotein, the cellular mediator of the MDR phenotype, was increased > 20-fold in the unstimulated MCF-7-MDR cell line and its phosphorylation was further increased 2-fold in response to phorbol 12-myristate 13-acetate. These changes paralleled the increases in P-glycoprotein pump function and the MDR phenotype underscoring the role for PKC alpha in regulating P-glycoprotein phosphorylation and function.
...
PMID:Selective regulation of expression of protein kinase C (PKC) isoenzymes in multidrug-resistant MCF-7 cells. Functional significance of enhanced expression of PKC alpha. 809 47

In our efforts to identify clinically effective drugs for reversing multidrug resistance (MDR) mediated by P-glycoprotein, we tested terfenadine for anti-MDR activity because it appeared to sensitize a patient to doxorubicin and because it met structural requirements defined for this activity. Terfenadine sensitized MCF-7/ADR human breast cancer cells and L1210/VMDRC.06 murine leukemia cells to doxorubicin. At concentrations < or = 10 microM, terfenadine decreased the IC50 to doxorubicin by up to 25-fold against MCF-7/ADR cells and completely restored sensitivity to L1210/VMDRC.06 cells. The drug had no effect on the sensitive, parental cell lines and enhanced activity of other drugs affected by the MDR phenotype. Terfenadine was as potent as trans-flupenthixol, one of the most active modulators of MDR. The mechanism of action of terfenadine appeared to be due to inhibition of the function of P-glycoprotein since it augmented the accumulation of doxorubicin and inhibited the efflux of rhodamine 123 from MDR lines but had no effect on drug accumulation or efflux in sensitive cells. Terfenadine displaced azidopine from P-glycoprotein, but at concentrations higher than expected based on its overall potency. Since terfenadine is clinically available, has numerous structural derivatives available for study, and has a relatively low toxicity profile, this drug and drugs of its class should be evaluated for future clinical trials.
...
PMID:Terfenadine (Seldane): a new drug for restoring sensitivity to multidrug resistant cancer cells. 809 15

Multidrug resistance is functionally associated with the expression of a plasma membrane energy-dependent drug efflux pump termed P-glycoprotein, the product of the mdr1 gene. Transfection of P-glycoprotein-expressing doxorubicin-resistant MCF-7 cells with an expression vector containing the cDNA for protein kinase C alpha in the antisense orientation reduces protein kinase C alpha levels and decreases total protein kinase C activity by 75%. This is accompanied by reduced phosphorylation of P-glycoprotein, a 2-fold increase in drug retention, and a 3-fold increase in doxorubicin cytotoxicity. These results provide further evidence that protein kinase C alpha can positively regulate multidrug resistance in MCF-7 cells through posttranslational phosphorylation of P-glycoprotein.
...
PMID:Expression of the antisense cDNA for protein kinase C alpha attenuates resistance in doxorubicin-resistant MCF-7 breast carcinoma cells. 810 Mar 51

Multidrug resistance (MDR) is frequently found in haematologic malignancies. It has been shown that MDR is often related to the expression of a membrane glycoprotein (P-170) which actively pumps many hydrophobic agents out of the cells. Previous electron microscopic investigations revealed morphological differences between P-388 resistant and P-388 sensible cell membranes, but the modulation of the membrane morphology seems to be related to the tumor-cell environment. In order to establish if morphological differences exist between sensitive and resistant cells, both sensitive and resistant strains from three different cell lines were studied by scanning electron microscopy: human leukaemia CEM and vinblastine resistant cells (CEM/VBL100), human breast cancer MCF-7 and mice leukaemia P-388 with the doxorubicin resistant strains (MCF-7/DX and P-388/DX, respectively). The surface of the membranes of the sensitive cells was regular, unlike the resistant ones which proved to be irregular, endowed with long villus-like processes or numerous folds and ruffles. The addition of albumin to the culture medium induced a shift from the resistant to the sensitive phenotype, thus suggesting that the P-388/DX morphology may be linked to the concentration of protein in the culture medium. Exposure to DX, verapamil (VRP) or monoclonal antibody against P-170 (mAb-57) did not modify the surface of the resistant strains, demonstrating that surface irregularities are probably not linked to P-glycoprotein function. Blasts from four P-170 positive leukaemic patients were also analyzed: an irregular shape was always found.
...
PMID:Scanning electron microscopy of multidrug resistant cells in haematological and mammary malignancies. 810 68

This study examined whether levels of estrogen receptor (ER), progesterone receptor (PR), and expression of estrogen regulated pS2 and/or heat shock protein (hsp) 27 were associated with drug resistance in a series of MCF-7 sublines expressing modest (i.e. 3- to 14-fold), yet clinically relevant, levels of resistance to vincristine (VCR). These sublines were variously derived following pulsed exposures to VCR, to fractionated X-irradiation, or to alternating drug and X-ray treatments. This selection procedure more closely reflects the clinical treatment of breast tumors than the use of continuous drug exposures. The drug-selected sublines exhibited the classical multidrug resistance phenotype (MDR) characterized by cross-resistance to vinblastine (VLB), etoposide (VP-16), and Adriamycin (ADR), overexpression of P-glycoprotein (Pgp), impaired accumulation of [3H]-VCR and of Rhodamine-123 (Rh 123), and altered activities of certain drug detoxification enzymes. This classic MDR phenotype was associated with a lack of mitogenic response to estrogen or antiestrogen, related to loss of detectable ER and PR; consistent with these data, neither pS2 nor hsp27 expression was detectable. In contrast, X-ray-pretreated VCR-resistant cells (MCF/DXR-10) cells exhibited a distinctive resistance phenotype proving cross-resistant to VLB and VP-16 but not to ADR, and Pgp overexpression was not detectable. Furthermore, these VCR-resistant DXR-10 cells retained parental levels of ER and PR, exhibited sensitivity to estrogen and 4-hydroxytamoxifen, and expressed detectable levels of pS2 and hsp27. Comparable characteristics to these MCF-7/DXR-10 cells were also identified in a similarly-derived X-ray-pretreated VCR-resistant subline of the ZR-75-1 human breast tumor cell line. These data therefore indicate that functional ER are frequently, but not invariably, modified in tumor cells which express resistance to multiple drugs.
...
PMID:Differential expression of steroid receptors, hsp27, and pS2 in a series of drug resistant human breast tumor cell lines derived following exposure to antitumor drugs or to fractionated X-irradiation. 840 Mar 21


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---