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)

Reversal of the drug resistance phenotype by the use of agents which induce cell differentiation offers an experimental approach to the study of chemoresistance. In numerous in vitro models, alpha-interferon (alpha-IFN) has been shown to induce phenotypical changes and to modulate the growth of cancer cells. The aim of the present study was to define the effect of alpha-IFN on the Adriamycin sensitivity of the human colon adenocarcinoma cell line, LoVo, and its Adriamycin-resistant variant, LoVo/DX. Pretreatment of LoVo/DX cells with 500 units/ml of alpha-IFN increased sensitivity to low doses of Adriamycin. Similar treatment conditions did not change the sensitivity of the parental cell line. Following treatment of the LoVo/DX cells with alpha-IFN plus 100 ng/ml Adriamycin for 1 h, 30% of the cells survived compared to 100% of untreated cells. This effect was not related to changes in cell cycle kinetics induced by alpha-IFN treatment and did not result from variations in the expression of P-glycoprotein at the cell surface, as assessed by flow cytometric analysis using monoclonal antibody MRK16. Adriamycin accumulation was increased by alpha-IFN as assessed by spectrofluorometric analysis. Thus, the data suggest that in LoVo/DX cells, alpha-IFN increased Adriamycin cytotoxicity through modulation of the multidrug resistance phenotype.
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PMID:Reversal of adriamycin resistance by recombinant alpha-interferon in multidrug-resistant human colon carcinoma LoVo-doxorubicin cells. 189 80

Human multidrug-resistant cells, K562/ADM, KB-C-4, AdrRMCF-7 and CEM/VLB100 showed 21-, 7.5-, 105- and 3.4-fold cross-resistance to mitomycin C (MMC). The resistance to MMC in K562/ADM, KB-C-4, AdrRMCF-7, CEM/VLB100 cells was reversed by 6.6 microM verapamil. Accumulation of [3H]MMC in K562/ADM, AdrRMCF-7 and CEM/VLB100 cells also decreased by 37, 26 and 33%, as compared with their drug-sensitive counterparts. In KB-C-4 cells, accumulation of [3H]MMC decreased by 60%, and efflux rate of [3H]MMC was slightly increased as compared to their parental KB-3-1 cells. Verapamil at 6.6 microM increased accumulation of [3H]MMC in these multidrug-resistant sublines. K562/ADM10, K562/ADM50, K562/ADM100 and K562/ADM250 cells, which showed 17- to 230-fold resistance to Adriamycin, also showed 0.8- to 7.3-fold cross-resistance to MMC. In these cell lines, the extent of resistance to Adriamycin (ADM) that was consistent with expression levels of P-glycoprotein shown by immunoblotting was directly proportional to the extent of their resistance to MMC. Regression analysis indicated that relative resistance to Adriamycin was correlated with relative resistance to MMC (r = 0.98). These results indicate that MMC can be transported by P-glycoprotein overexpressed in multidrug-resistant cells.
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PMID:Cross-resistance of human multidrug-resistant cells to mitomycin C. 190 15

In a previous study we suggested that, in addition to the reduced Adriamycin accumulation, part of the resistance in an Adriamycin-resistant human small cell lung carcinoma cell line (GLC4/ADR) could be explained by supposing a changed Adriamycin-DNA-topoisomerase II (Topo II) interaction. The present study showed that the Mr 170,000 P-glycoprotein was not overexpressed in GLC4/ADR and that verapamil did not reverse the Adriamycin resistance. GLC4/ADR expressed cross-resistance to teniposide, etoposide, 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), and mitoxantrone. Further investigations of the drug-Topo II interaction revealed that the decatenation activity of Topo II was two- to threefold reduced in both cellular and nuclear extracts from GLC4/ADR. Topo I activities appeared similar in extracts from GLC4/ADR and the parental sensitive cell line (GLC4). The slight increase in doubling time from 15 to 18 h, while the cell cycle distribution remained unchanged, could not account for the reduced Topo II activity in GLC4/ADR. Etoposide and m-AMSA-induced DNA cleavage was 5-fold reduced in cellular extracts from GLC4/ADR. Inhibition of the decatenation activity of Topo II in the presence of VP-16 and m-AMSA was increased twofold in the cellular extracts from GLC4/ADR. Therefore, these results suggest that resistance of GLC4/ADR to Adriamycin was in part due to the reduced drug-induced formation of the cleavage complex.
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PMID:Reduced DNA topoisomerase II activity and drug-induced DNA cleavage activity in an adriamycin-resistant human small cell lung carcinoma cell line. 196 22

HL60 cells isolated for resistance to Adriamycin are multidrug resistant and defective in the cellular accumulation of drug. These cells do not however overexpress mdr1 and do not contain detectable levels of P-glycoprotein. In the present study we have prepared antisera against synthetic peptides that correspond to various sequence domains of P-glycoprotein and have examined by Western blot analysis the reactivity of these antisera with proteins contained in membranes of HL60/Adr cells. All antisera are highly reactive with a Mr 180,000 (p180) P-glycoprotein contained in membranes of HL60 cells isolated for resistance to vincristine (HL60/Vinc). In contrast, of 13 antisera tested 12 do not react with any resistance-associated protein in the HL60/Adr isolate. One antiserum (ASP14) is however highly reactive with a Mr 190,000 protein (p190) contained in HL60/Adr membranes. This protein is not detected in drug-sensitive cells. ASP14 also reacts with proteins p195 and p50 contained in a second independent HL60/Adr isolate. Analysis of membrane subfractions shows that p190 is located primarily in the endoplasmic reticulum with only low levels contained in plasma membranes. Additional studies demonstrate that endoplasmic reticulum of HL60/Adr cells contain a major Mr 190,000 protein that is capable of binding the photoaffinity agent 8-azido[alpha-32P]ATP. p195 contained in a second HL60/Adr isolate is also labeled with 8-azido[alpha-32P]ATP. These results thus demonstrate that antiserum against a specific P-glycoprotein sequence detects a p190 (p195) resistance-associated membrane protein in two independent HL60/Adr isolates. p190 (p195) and P-glycoprotein thus contain a minor sequence homology and based on the specificity of ASP14 this occurs in a region which may be involved in nucleotide binding. Possibly this sequence is common to and essential for the functionality of proteins which contribute to resistance by reducing cellular drug levels.
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PMID:Mechanisms of multidrug resistance in HL60 cells: detection of resistance-associated proteins with antibodies against synthetic peptides that correspond to the deduced sequence of P-glycoprotein. 196 79

One thousand fungi and Actinomycetes were investigated to see whether they produced compounds that reverse multi-drug resistance in KB cells. Only one Aspergillus strain M39 produced agents with resistance-reversing activity and these compounds were identified to be rubrofusarin B and dianhydro-aurasperone C. Rubrofusarin B only slightly reversed the resistance of KB-C2 cells to Adriamycin and daunomycin, partially reversed the resistance to chromomycin A3, and almost completely reversed the resistance to vincristine and mitomycin C. Purified dianhydro-aurasperone C and rubrofusarin B had similar effects on drug resistance in KB-8-5 cells. Dianhydro-aurasperone C enhanced the accumulation of vinblastine in KB-8-5 cells and inhibited the efflux of vinblastine from the cells. Dianhydro-aurasperone C and rubrofusarin B at 10 microM completely inhibited 3H-azidopine photolabelling of P-glycoprotein. The two products of Aspergillus strain M39 appear to reverse multi-drug resistance by interacting with P-glycoprotein and inhibiting its role as an active efflux pump.
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PMID:Aspergillus species strain M39 produces two naphtho-gamma-pyrones that reverse drug resistance in human KB cells. 196 38

One of the characteristics of multidrug-resistant mammalian cells is the presence of a glycoprotein of approximately Mr 170,000 in their cell membrane. Termed P-glycoprotein, this glycoprotein is thought to be the gene product of an amplified gene cloned and sequenced from a cell line (LZ) which is highly resistant to Adriamycin and cross-resistant to actinomycin D, colchicine, and vincristine. Resistance to Adriamycin has been induced in sensitive cells by chromosome or gene transfer. We now show that P-glycoprotein isolated from LZ cells and fused to sensitive V79 Chinese hamster cells renders the latter transiently resistant to Adriamycin. Incorporation of P-glycoprotein was confirmed by immunoperoxidase staining of fusion products following treatment with antibody to P-glycoprotein and by Western blots of membrane preparations from fusion products. These results suggest that P-glycoprotein is one of the important factors in the expression of Adriamycin resistance and provide added confirmation that it may be the important product of gene amplification in multidrug-resistant cells. The results also suggest that the cell membrane may be one of several targets for Adriamycin cytotoxicity and that P-glycoprotein may be a binding site for Adriamycin, rendering the latter ineffective in registering sufficient membrane damage for cell killing.
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PMID:Transfer of adriamycin resistance by fusion of Mr 170,000 P-glycoprotein to the plasma membrane of sensitive cells. 196 29

The interaction of etoposide (VP-16), Vinca alkaloids, and verapamil with the P-glycoprotein (P-gp) was studied in human breast (MCF-7) and Chinese hamster lung (DC3F) cell lines and the corresponding multidrug-resistant MCF-7/ADR and DC3F/ADX tumor cell lines, selected for resistance to Adriamycin and actinomycin D, respectively, and overexpressing P-gp. Verapamil (10 microM) markedly reversed resistance to vincristine (11-fold in DC3F/ADX and 125-fold in MCF-7/ADR; 1-hr exposure), but it had a very modest effect on resistance to VP-16 (3- to 4-fold; 1-hr exposure). Resistant cells accumulated 2- to 4-fold less VP-16 and vincristine than the parental cell lines. Verapamil (10 microM) significantly increased accumulation and retention of vincristine, but not of VP-16, in resistant cell lines. Photoaffinity labeling of resistant cell lines with radioactive analogs of verapamil [N(p-azido-3-125I-salicyl)-N'-beta-aminoethylverapamil (NASVP)] and vinblastine[N-(p-azido-3-125I-salicyl)-N'-beta-aminoethylvindesine (NASV)] showed distinctly labeled P-gp bands in both resistant cell lines, compared with wild-type cells. Excess nonradioactive vinblastine or verapamil effectively competed with the P-gp photolabeling by either NASVP or NASV, with IC50 levels of 0.6 and 10 microM, respectively. In contrast, nonradioactive VP-16 was 100- to 500-fold less potent than vinblastine in competing with P-gp photolabeling, suggesting that VP-16 has significantly lower affinity for P-gp than Vinca alkaloids have. Taken together, our data indicate that P-gp glycoprotein by itself may not be important in the transport/efflux of VP-16 and, thus, in the mechanism of resistance to VP-16 in these cells.
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PMID:P-glycoprotein-independent mechanism of resistance to VP-16 in multidrug-resistant tumor cell lines: pharmacokinetic and photoaffinity labeling studies. 197 71

A number of recent studies have implied that a relationship exists between cellular sensitivities to tumor necrosis factor (TNF) and expression of the classic multidrug resistance (MDR) phenotype. However, different conclusions have been reported concerning whether TNF sensitivity is positively or negatively correlated with MDR (Hong, W.-S.; Sijo, N.; Sasaki, Y.; Shinkai, T.; Eguchi, K.; Sakurai, M.; Takamashi, H.; Nakano, H.; Nakagawa, K.; Twentyman, P. R. Jpn. J. Can. Res. (Gann) 78:1274-1280; 1987 and Dollbaum, C.; Creasey, A. A.; Dairkee, S. H.; Hiller, A. J.; Rudolph, A. R.; Lin, L.; Vitt, C.; Smith, H. S. Proc. Natl. Acad. Sci. USA 85:4740-4755; 1988). An apparent relationship of TNF sensitivity to P-glycoprotein (P-170gp) mediated MDR was investigated in EL4 murine T-lymphoma cell lines sensitive and resistant to Adriamycin (ADM). No consistent association was found between MDR and TNF responses when the lines were subcloned. Whereas the MDR phenotype of subclones (as assessed by ADM resistance and P-170gp expression) reflected that of the cell line from which they were derived, the TNF sensitivity of subclones varied widely. Also consistent with independence of P-170gp mediated MDR and TNF response, the P388/ADM cell line (exhibiting P-170gp mediated MDR) remained as resistant to TNF as the P388 parental line. In addition, no evidence was found of modified recognition of MDR EL4 cell lines by host defense effector cells, and gamma-interferon failed to enhance the susceptibility of either parental or MDR cell line to TNF. These results may be of value in considering therapeutic studies using the ADM/TNF combination treatment.
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PMID:The relationship between multidrug resistance and tumor necrosis factor resistance in an EL4 cell line model. 197 58

A newly established gastric carcinoma cell line (EPG85-257P) exhibited a high sensitivity to mitoxantrone (DHAD) as determined by a monolayer proliferation assay. The concentration to inhibit cell growth to 50% of controls (IC50) was 0.0022 micrograms/ml culture medium. The cells were continuously incubated for more than 4 months in the presence of stepwise increased concentrations of DHAD, and the IC50 was increased to 0.41 micrograms/ml, i.e., 186.4-fold. This resistant variant was named EPG85-257RNOV. The EPG85-257RNOV cells became cross-resistant to Adriamycin with enhanced IC50 by 10.5-fold and to daunomycin with enhanced IC50 by 3.9-fold. No distinct resistance was observed to vinblastine, vincristine, and colchicine. Verapamil (10(-6), 4 X 10(-6) and 10(-5) M) and cyclosporin A (10(-6), 3 X 10(-6) and 10(-5) M) did not reverse DHAD resistance. As shown by immunocytochemistry (monoclonal antibodies: C219 and JSB-1) and Northern blot analysis, DHAD resistance was not associated with the appearance of the multidrug resistance (MDR)-associated (Mr 170,000) P-glycoprotein or the overexpression of P-glycoprotein mRNA. The data indicate a chemoresistance pattern unlike typical MDR (often called "atypical" MDR). The phenotypes of parent and resistant EPG85-257 cells were compared using interference contrast microscopy, electron microscopy, and immunocytochemistry. After DHAD application the following structural characteristics were found to be associated with emergence of resistance: (a) intensive formation of surface vesicles in the resistant variant. Such vesicles were almost absent in sensitive cells; (b) the vesicles contained the selecting DHAD which was visualized by its blue color; and (c) in electron microscopy the vesicles were formed by an inner and an outer double membrane, presumably derived from the plasmalemma. These observations suggest a complex cellular mechanism responsible for DHAD resistance which includes formation of membrane vesicles, vesicular drug binding, and drug compartmentalization.
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PMID:Membrane vesicle formation due to acquired mitoxantrone resistance in human gastric carcinoma cell line EPG85-257. 197 14

We established an etoposide (VP-16)-resistant human small-cell lung cancer cell line (H69/VP) by stepwise exposure to VP-16. The resistance of H69/VP to VP-16 was 9.4-fold that of the parent cell line (H69/P). H69/VP showed cross-resistance to Adriamycin (ADM), (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy]-1H-pyrano[3',4':6,7]indolizino [1,2-b]quinoline-3,14(4H,12H)-dionehydrochloride trihydrate (CPT-11), teniposide (VM-26), vindesine (VDS) and vincristine (VCR). The amount of DNA topoisomerase II (topo.II) was nearly the same in H69/P and H69/VP cells. The catalytic activity of topo.II in H69/VP cells was lower than that in the H69/P line. Accumulation of [3H]-VP-16 in H69/VP was 6.1-7.5 times lower than that in H69/P. According to Northern blot analysis, the mdr-1 mRNA level in H69/VP was markedly higher than that in H69/P. These findings suggest that H69/VP has a typical multidrug resistance (MDR) phenotype and that alteration of the drug accumulation mediated by P-glycoprotein may play an important role in resistance to VP-16. Reduced topo.II activity may also be associated with VP-16 resistance.
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PMID:Characterization of an etoposide-resistant human small-cell lung cancer cell line. 197 50


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