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)

Effect of specific inhibitors of extracellular-signal regulated protein kinase (ERK) pathway, PD98059 and U0126, on P-glycoprotein (Pgp)-mediated vincristine resistance of L1210/VCR cells was investigated. Both test inhibitors significantly reduced the survival of L1210/VCR cells in the presence of vincristine and this was associated with a decrease of LC50 values to vincristine from 2.65+/-0.43 to 0.67+/-0.28 micromol/l and to 0.69+/-0.09 micromol/l after treatment with 50 micromol/l PD98059 and 25 micromol/l UO126, respectively. Moreover, the effects of PD98059 are connected also with an increased intracellular accumulation of radiolabeled vincristine in resistant L1210/VCR cells in concentration dependent manner. The results of this study demonstrate that inhibitors of ERK signaling pathway are reversal agents of vincristine resistance in L1210/VCR cells. The precise mechanism of PD98059 and U0126 action in modulation of MDR is not resolved yet, but the role of ERK-mediated phosphorylation cascade could be considered.
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PMID:Reversal effect of specific inhibitors of extracellular-signal regulated protein kinase pathway on P-glycoprotein mediated vincristine resistance of L1210 cells. 1198 53

To find a drug to overcome P-glycoprotein associated multidrug resistance, we synthesized 43 new isoprenoid derivatives. Ten compounds were effective in an in vitro assay with the human MDR-type resistant carcinoma KB/VJ-300 and MRP-type KB/VP-4 cell lines. One of the most effective compounds, N-5228 [trans-N,N'-bis(3,4-dimethoxybenzyl)-N-solanesyl-1,2-diaminocyclohexane, mol. wt 1100.481, was tested in P388/VCR-bearing mice. It showed a antitumor effect on MDR-type resistant tumor cells. Moreover, N-5228 potentiated the accumulation of [3H]vincristine in drug-resistant cells and blocked [3H]azidopine photoaffinity labeling of P-glycoprotein molecules in MDR-type resistant cell membranes. We think that N-5228 is promising as a lead compound in the screening of resistance reversing drugs for multidrug resistant cancers.
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PMID:Reversal of P-glycoprotein associated multidrug resistance by new isoprenoid derivatives. 1204 84

To explore whether human umbilical cord blood hematopoietic progenitor cells transduced with human O6-methylguanine-DNA-methyltransferase (MGMT) and multidrug resistance gene (MDR1) increase resistance to 1,3-Bis(2-Chloroethy1)-1-Nitrosourea (BCNU) and P-glycoprotein effluxed drugs, the present authors obtained a full length cDNA fragment encoding MGMT from liver tissue of a patient with cholelithiasis by RT-PCR. A bicistronic retroviral vector G1Na-MGMT-IRES-MDR1 cDNA was constructed and transfected the packaging cell lines GP + E86 and PA317 by electric performation method, using the medium containing VCR and BCNU for cloning selection and ping-ponging supernatant infection between ecotropic producer clone and amphotropic producer clone, cord blood CD34+ cells were enriched with a high-gradient magnetic cell sorting system (MACS), and then transfected repeatedly with supernatant of retrovirus containing human MGMT and MDR1cDNA under stimulation of hemapoietic growth factors. PCR, RT-PCR, Southern blot, Northern blot, Western blot, FACS and MTT assay were used to evaluate the transfer and expression of the double genes in cord blood CD34+ cells. The cDNA encoding MGMT was verified by DNA sequencing and the bicistronic retroviral vector was confirmed by restriction endonuclease analysis. The purity of cord blood CD34+ cells was approximately 92% and recover rate was 75%, the highest titer of recombinant amphotropic retrovirus in the supernatant was up to 5.8 x 10(5) cfu/ml. The efficiency of gene transduction was 18% and 20% tested by colony formation and PCR, respectively. No helper virus was found by both nested PCR and rescue assay. The results showed that dual drug resistance genes have been integrated into the genomic DNA of cord blood CD34+ cells and expressed efficiently. The MTT analysis showed a 4.5 to 7.8-fold increase of resistance of transducted cells to BCNU and P-glycoprotein effluxed drug as compared with the nontransduced cells. This study provided a foundation for ameliorating combination chemotherapy toxicity in tumor clinical trial.
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PMID:[A bicistronic retroviral vector containing MGMT and MDR1 drug resistance genes transfer into human umbilical cord blood CD34+ cells to improve combination chemotherapy tolerance]. 1254 25

Multidrug resistance of murine leukaemic cell line L1210/VCR (obtained by adaptation of parental drug-sensitive L1210 cells to vincristine) is associated with overexpression of mdr1 gene product P-glycoprotein (Pgp)-the ATP-dependent drug efflux pump. 31P-NMR spectra of L1210 and L1210/VCR cells (the latter in the presence of vincristine) revealed, besides the decrease of ATP level, a considerable lower level of UDP-saccharides in L1210/VCR cells. Histochemical staining of negatively charged cell surface binding sites (mostly sialic acid) by ruthenium red (RR) revealed a compact layer of RR bound to the external coat of sensitive cells. In resistant cells cultivated in the absence or presence of vincristine, the RR layer is either reduced or absent. Consistently, resistant cells were found to be less sensitive to Concanavalin A (ConA). Moreover, differences in the amount and spectrum of glycoproteins interacting with ConA-Sepharose were demonstrated between sensitive and resistant cells. Finally, the content of glycogen in resistant cells is lower than in sensitive cells. All the above facts indicate that multidrug resistance of L1210/VCR cells mediated predominantly by drug efflux activity of Pgp is accompanied by a considerable depression of oligo- and/or polysaccharides biosynthesis.
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PMID:P-glycoprotein-mediated multidrug resistance phenotype of L1210/VCR cells is associated with decreases of oligo- and/or polysaccharide contents. 1463 53

ZNRD1, a new zinc ribbon gene, has been previously identified as an upregulated gene in a multidrug-resistant gastric cancer cell line SGC7901/VCR comparing to its parental cell SGC7901 by subtractive hybridization and RT-PCR. The antisense nucleic acid for ZNRD1 could enhance adriamycin accumulation in SGC7901/VCR cells and sensitize SGC7901/VCR cells to vincristine. The present study aims to explore the role of ZNRD1 in multidrug resistance in gastric cancer cells. Upregulation of ZNRD1 protein in SGC7901/VCR cells was confirmed by Western blot and immunocytochmical staining. ZNRD1 was genetically overexpressed in SGC7901 cells by gene transfection. It was found that overexpression of ZNRD1 could sensitize SGC7901 cells to P-glycoprotein (P-gp)-related anticancer drugs (vincristine, adriamycin, etoposide) but not to P-gp-nonrelated drugs (5-fluorouracil and cisplatin), which was accompanied with significantly decreased adriamycin accumulation and retention and increased adriamycin releasing in SGC7901 cells. Verapamil, an inhibitor for P-gp, could reverse the effects of ZNRD1 on drug sensitivity and drug accumulation in SGC7901 cells to a great extent. Western blot and Northern blot revealed that overexpression of ZNRD1 could upregulate P-gp at both protein and mRNA levels. Together, these results suggest that overexpression of ZNRD1 could promote multidrug-resistant phenotype of gastric cancer cells through upregulation of P-gp.
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PMID:Overexpression of ZNRD1 promotes multidrug-resistant phenotype of gastric cancer cells through upregulation of P-glycoprotein. 1497 23

In our previous papers we described the ability of methylxanthine pentoxifylline (PTX) to depress the P-glycoprotein (P-gp) mediated multidrug resistance (MDR) of the mouse leukemic cell line L1210/VCR. Other methylxanthines like caffeine and theophylline were found to be ineffective in this respect. In the present paper we have analysed the capability of 25 methylxanthines to depress MDR of L1210/VCR cells. These methylxanthines structurally differ in substituents located in positions N1, N3, N7 and C8. The results indicate that for an effective reversal of P-gp mediated MDR of our cells the existence of a longer polar substituent in the position N1 plays a crucial role. The elongation of the substituent in the positions N3 and N7 (from methyl to propyl) increases and in the position C8 (from H to propyl) decreases the efficacy of xanthines to reverse the vincristine resistance of L1210/VCR cells. The multiple linear regression for effectiveness of methylxanthines in reversal of P-gp mediated MDR of L1210/VCR cells (expressed as respective IC(50r) values) has been computed, with molar weight: M(w), molar volume: V(M), molar refractivity: R(M), crystal density: d and partition coefficient n-octanol/water: logP as descriptors. A high intercorrelation of M(W), V(M) and R(M) was found for the tested group of methylxanthines indicating that only one of these parameters is necessary for testing a potential correlation. The best fit in the multiple linear regression was obtained for R(M) applied together with d and logP and resulted in a QSAR model given by the following equation: IC(50r)=-[(32.3+/-7.2)x10(-3)xR(M)]+[(10.1+/-2.3)xd]+[(0.74+/-0.10)xlogP]-[10.5+/-3.2]. Model revealed that: (i) the molar refractivity influences the effectiveness of xanthine positively; (ii) the crystal density and partition coefficient influence the MDR reversal effectiveness of xanthine negatively.
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PMID:Reversal of P-glycoprotein mediated vincristine resistance of L1210/VCR cells by analogues of pentoxifylline. A QSAR study. 1475

The cytotoxic effects on HCT 116, Hep G2 and HCT 116/VCR 100-1-1 cell lines of synthetic 4'-O-alkylaloenins (2-17), 4'-O-benzylaloenin (18) and 4'-O-allylaloenin (19) were examined by MTT assay, and compared with that of aloenin (1) isolated from Aloe arborescens Mill. Var. natalensis Berger which showed no marked effect (IC50 value: > 100 microM). The cytotoxic effects of 4'-O-alkylaloenin sulfates (21-29) were also examined on the same cell lines. The introduction of a longer alkyl group at the O-4' position of 1 resulted in a higher cytotoxic action on HCT 116 and Hep G2 cells. Among 4'-O-alkylaloenins 2-17, 4'-O-tetradecylaloenin 14 was the most cytotoxic to both on HCT 116 cells (IC50 value: 5.3+/-2.3 microM) and Hep G2 cells (IC50 value: 4.0+/-0.6 microM). Also among 4'-O-alkylaloenin sulfates 21-29, 4'-O-dodecylaloenin sulfate 29 was the most cytotoxic to both on HCT 116 (IC50 value: 4.8+/-0.2 microM) and Hep G2 cells (IC50 value: 4.0+/-0.5 microM). 4'-O-Alkylaloenins 7-14 and 4'-O-alkylaloenin sulfates 24-29 were also cytotoxic to Hep G2 and HCT 116/VCR 100-1-1 cell lines, which overexpress P-glycoprotein, as well as HCT 116 cell lines which scarcely express it.
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PMID:4'-O-Alkyaloenin derivatives and their sulfates directed toward overcoming multidrug resistance in tumor cells. 1563 36

Flavonoids and their in vivo metabolites are neuroprotective, cardioprotective and chemopreventive agents acting as hydrogen-donating antioxidants or modulators functioning at protein kinase and lipid signaling pathways. In presented study treatments of human leukemia cells HL60 and their MDR-1 resistant subline HL60/VCR by flavonoids apigenin (API), luteolin (LUT), quercetin (QU) and anticancer drug doxorubicin (DOX) are reported. Of all flavonoids used only QU treatments led in both cell lines to DNA fragmentation, cleavage of poly (ADP- ribose) polymerase (PARP), up-regulation of proapoptotic Bax and posttranslational modification (phosphorylation) of antiapoptotic Bcl-2. Cytochrome c and p21WAF1/CIP1 levels remained unchanged in these cells. Furthermore, treatments of both cell lines by QU and in its combined application with DOX increased phosphorylation of ERK, while Akt-1 and phosphorylated Akt-1 levels were not changed. All these events resulted in effective induction of apoptosis associated with down-regulation of P-glycoprotein in resistant cells. Presented results suggest that in human leukemia cells QU is a potent regulator of the cell apoptotic program associated with the modulation of several signaling molecules.
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PMID:Flavonoid quercetin, but not apigenin or luteolin, induced apoptosis in human myeloid leukemia cells and their resistant variants. 1605 41

L1210/VCR cell line (R) was obtained by adaptation of the L1210 mouse leukaemia cells (S) to vincristine and showed P-glycoprotein (P-gp) mediated multidrug resistance (MDR). R cells were observed to be more sensitive to high external calcium as parental S. More pronounced calcium uptake was observed for R cells. Moreover, differences in intracellular calcium cell localization between S and R cells were found ultrastructurally following a calcium precipitating cytochemical method. In S cells, calcium precipitates were found to be localized predominantly along the cell surface coat and within mitochondria delineating the cristae. In R cells, precipitates were also found inside nuclei, at the border of heterochromatin clumps, and scattered within the cytoplasm. High extracellular calcium did not influence the P-gp mediated extrusion of calcein/AM as P-gp substrate. These results indicate that calcium enters and consequently damages the MDR cells to a higher extent than parental cells.
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PMID:Expression of P-glycoprotein in L1210 cells is linked with rise in sensitivity to Ca2+. 1609 80

Multistep tumorigenesis is a form of microevolution consisting of mutation and selection. To clarify the role of selection modalities in tumor development, we examined two alternative evolutionary conditions, r-selection in sparse culture, which allows cells to proliferate rapidly, and K-selection in confluent culture, in which overcrowding constrains cell proliferation. Using MYC- and EJ-RAS-transformed rat embryo fibroblasts, we found that K-selected cells acquired and stably maintained multidrug resistance (MDR) to DOX, VCR, MTX and Ara-C. Then, we examined the involvement of a number of factors potentially causal of the development of MDR, that is, ploidy, Tp53 mutation, doubling time and the expression levels of genes related to drug resistance. Although ploidy status and Tp53 mutations did not correlate with MDR, we found that Abcb1/Mdr1, encoding P-glycoprotein (Pgp), was significantly upregulated after K-selection. Cyclosporin A, a competitive inhibitor of Pgp, increased the intracellular accumulation of DOX and reduced the resistance to it. Indeed, the population of Pgp-transfected cells significantly expanded under K-, but not under r-selection. In addition to Pgp upregulation, altered expression of other genes such as Cda/cytidine deaminase and Slc29a1/equilibrative nucleoside transporter 1 and prolonged doubling times were associated with MDR. This system reproduces events associated with MDR in vivo and would be useful for analysis of MDR development.
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PMID:Development of multidrug resistance due to multiple factors including P-glycoprotein overexpression under K-selection after MYC and HRAS oncogene activation. 1635 56


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