Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Resistance may limit the clinical usefulness of a variety of chemotherapeutic drugs including mitomycin C (MMC). The MMC-sensitive HT-29 colon cancer cell line and its MMC-resistant subline, HT-29R13, were studied in vitro under aerobic conditions to help characterize the mechanisms associated with MMC resistance. HT-29R13 cells exhibit approximately 2-fold resistance to MMC compared with HT-29 cells and lack the typical multidrug-resistance pattern; resistance is stable in the absence of drug exposure. Levels of glutathione (GSH) and total glutathione-S-transferase (GST) activity were not different between the two cell lines; however, levels of GSH reductase and GSH peroxidase were increased significantly in HT-29R13. Although total GST activity was unchanged, GST-pi and GST-alpha isoenzyme expression as measured using western blot were increased significantly in HT-29R13 compared with HT-29. DT-diaphorase levels and topoisomerase II activity were decreased significantly in HT-29R13. Both cell lines had equal P-glycoprotein expression. Multiple drug resistance mechanisms are present in HT-29R13 including decreased drug activation (decreased DT-diaphorase), increased drug detoxification (increased GST-pi and GST-alpha, GSH reductase, GSH peroxidase), and decreased accessibility of DNA targets (decreased topoisomerase II). Further work will be necessary to determine the degree to which each of these mechanisms contribute to MMC resistance in this model.
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PMID:Biochemical characterization of a mitomycin C resistant colon cancer cell line variant. 790 34

Yoshida rat ascites hepatoma (AH) has several cell lines with a characteristic sensitivity to antitumor drugs. AH66 cells overexpressed 160-170 kDa P-glycoprotein (P-gp) in the membrane and glutathione-S-transferase placental form (GST-P) in the cytosol. AH44 cells did not express P-gp but contained GST-P isozyme, while normal rat liver had GST-(1,2) and-(3,4) classes. AH44 and AH66 cells were more resistant to chlorambucil (CLB) than AH66F cells, which are a variant cell line derived from AH66 cells and lacked both proteins. CLB-resistant AH44 and AH66 cells contained a high amount of glutathione (GSH) and higher GST activity than AH66F cells. Ethacrynic acid, a GST-P inhibitor, and buthionine sulfoximine, a GSH biosynthesis inhibitor, significantly decreased the CBL resistance of AH44 and AH66 cells without influencing the sensitivity of AH66F cells. The CLB resistance of these cell lines were hardly influenced by verapamil, a calcium channel blocker with P-gp antagonistic action, which significantly decreased the vinblastine resistance of AH66 cells. This study indicates that AH66 cells showed multiple drug resistance dependent on P-gp and GST-P isozyme and that the AH44 cell line was CLB resistant through the GSH/GST-P detoxification system. These hepatomas are useful for investigation of the drug resistance of hepatic carcinomas and development of counteracting drugs.
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PMID:Glutathione-S-transferase P-form dependent chlorambucil resistance in Yoshida rat ascites hepatoma cell lines. 791 Jan 11

The aim of this study was to characterize two cis-diamminedichloroplatinum(II) (CDDP) resistant cell lines established from human larynx carcinoma HEp2 cells through repeated treatments with increased CDDP concentrations. CK2 cells obtained by continuous treatments were more resistant to CDDP than CA3 cells obtained by acute treatments. The examination of growth characteristics showed that both CDDP resistant cells had doubling times identical to that of the parental cells, but had lower plating efficiency. The possible involvement of glutathione (GSH), glutathione transferases (GST), metallothioneins, P-glycoprotein and drug accumulation in CDDP resistance was examined. Glutathione contents were elevated in both CDDP resistant lines. However, neither GSH nor GST were involved in CDDP resistance. This was demonstrated by simultaneous incubation of parental and CDDP resistant cells with CDDP and specific inhibitors of GSH and GST alpha and pi (buthionine sulfoximine and ethacrinic acid). Similarly, verapamil, an inhibitor of P-glycoprotein, did not influence the sensitivity of parental and resistant cells to CDDP. As compared to the parental cells, CK2 cells became resistant and CA3 cells became sensitive to cadmium, indicating increased level of metallothioneins in CK2 cells, and reduced level in CA3 cells. Measurements of platinum contents in parental and CDDP resistant cells after 1, 3 and 6 hours exposure to 70 mumol CDDP showed reduction in platinum accumulation after each exposure time in CK2 cells, and after 6 hours exposure in CA3 cells. This study identified decreased platinum accumulation as an important mechanism of CDDP resistance in human larynx carcinoma cells.
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PMID:Human larynx carcinoma cells resistant to cis-diamminedichloroplatinum(II): mechanisms involved in the resistance. 793 85

The levels of several potential indicators of drug resistance were measured in tumor and corresponding normal tissue of 55 untreated patients with lung cancer. The resistance parameters include glutathione (GSH) level, activities of the enzymes glutathione transferase (GST), glutathione peroxidase (GPx) and O6-alkylguanine-DNA alkyltransferase (ATase), as well as expression of P-glycoprotein (Pgp). Median values of GSH, GST and GPx were significantly higher in tumor than in normal tissue of non-small-cell lung cancer (NSCLC) or of small-cell lung cancer (SCLC), whereas ATase was elevated in tumor tissue of NSCLC only. Pgp expression as determined by Western blotting was significantly lower in tumor than in normal tissue of NSCLC. Resistance-parameter expression did not correlate with stage of disease or age of the patients. We found a negative correlation between smoking intensity and GSH level in normal tissue. Our findings indicate that the fundamental differences in chemosensitivity between SCLC and NSCLC cannot be explained by differences in the GSH-system or in the expression of Pgp. However, the level of ATase activity may be one of the factors responsible for the difference in chemosensitivity.
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PMID:Parallel assessment of glutathione-based detoxifying enzymes, O6-alkylguanine-DNA alkyltransferase and P-glycoprotein as indicators of drug resistance in tumor and normal lung of patients with lung cancer. 796 Feb 35

The ATP-dependent glutathione S-conjugate export pump, named GS-X pump, has been shown to eliminate a potentially cytotoxic glutathione-platinum (GS.Pt) complex from tumor cells, thereby modulating glutathione (GSH)-associated resistance to cis-diamminedichloroplatinum(II) (cisplatin) (Ishikawa, T., and Ali-Osman, F. (1993) J. Biol. Chem. 268, 20116-20125). The present study provides evidence that the GS-X pump is functionally overexpressed in cisplatin-resistant human promyelocytic leukemia HL-60 (HL-60/R-CP) cells, in which the cellular GSH level was substantially enhanced. Indeed, the rate of ATP-dependent transport of the GS.Pt complex, measured with plasma membrane vesicles, was about 4-fold greater in HL-60/R-CP cells than in HL-60 cells. Three membrane proteins with apparent molecular masses of 200, 110, and 70 kDa were overexpressed in HL-60/R-CP cells, whereas P-glycoprotein (MDR1) was not immunologically detected in the membrane preparations from resistant and sensitive cells. Unlike in HL-60 cells, increased numbers of intracellular vesicles were observed in the cytoplasm of HL-60/R-CP cells. Fluorescence microscopy with syn-(CICH2,CH3)-1,5-diazabicyclo-[3.3.0]-octa-3,6-dione-2,8-dione (monochlorobimane) revealed that the fluorescent glutathione S-conjugate accumulated in intracellular vesicles of the cisplatin-resistant cells in an energy-dependent manner. The GS-X pump is suggested to contribute to vesicle-mediated excretion of GSH-drug conjugates from cells. In addition, both HL-60 and HL-60/R-CP cells underwent cell differentiation in response to 12-O-tetradecanoylphorbol-13-acetate, retinoic acid, and dimethyl sulfoxide, resulting in proliferation arrest as well as a remarkable decrease in the c-myc mRNA levels. After cell differentiation, a significant decrease was observed in the activity of ATP-dependent transport of the GS.Pt complex in membrane vesicles prepared from both HL-60/R-CP and HL-60 cells. These results suggest that the expression of the GS-X pump in both cisplatin-resistant and -sensitive cells is related to cell proliferation.
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PMID:GS-X pump is functionally overexpressed in cis-diamminedichloroplatinum (II)-resistant human leukemia HL-60 cells and down-regulated by cell differentiation. 796 75

Small cell lung cancer (SCLC) is treated primarily with combination chemotherapy. Despite high initial response rates, most patients eventually die with drug resistant disease. In some tumours, resistance to multiple chemotherapeutic agents is attributed to overexpression of P-glycoprotein (P-gp). However, this does not appear to be a frequent occurrence in drug resistant SCLC. Increased levels of glutathione (GSH) and related enzymes may play a role in resistance to alkylating agents as well as natural product drugs. We measured levels of GSH, glutathione S-transferase (GST), glutathione reductase (GSH Red), glutathione peroxidase (GSH Px), and gamma-glutamyl transpeptidase (gamma-GT) in a panel of 20 SCLC cell lines. Most of these lines were established from patients treated at this centre. Each cell line had a characteristic and reproducible profile of GSH and related enzyme levels. Immunoblot analysis indicated that the predominant GST in the cell lines was the anionic pi isoenzyme. The relative sensitivity of each of these cell lines to 16 different chemotherapeutic agents was measured using a modified MTT assay. Spearman rank correlation analysis was used to determine the relationships between the relative chemosensitivity of these cell lines and the levels of GSH and related enzymes. The number of positive correlations was no greater than expected by chance alone. Furthermore, there was no correlation with the treatment history of the patients from whom the cell lines were derived. These data suggest that alterations in glutathione metabolism do not play a major role in resistance to chemotherapeutic agents in these human SCLC cell lines.
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PMID:Do glutathione and related enzymes play a role in drug resistance in small cell lung cancer cell lines? 810 44

Methylmercury transport across liver canalicular membranes into bile, a major route of excretion of this toxic compound, is dependent upon intracellular GSH, and a glutathione-methylmercury complex (CH3Hg.SG) has been detected in liver tissue and bile. To examine whether the CH3Hg.SG complex is itself transported across the canalicular membrane and to identify the transport system involved, studies were performed in isolated rat liver canalicular plasma membrane vesicles. Uptake of CH3(203)Hg.SG (10 microM) into an osmotically active space was temperature-sensitive and unaffected by either ATP (5 mM) or an inwardly directed Na+ gradient (100 mM); however, CH3Hg.SG uptake was enhanced by a valinomycin-induced K+ diffusion potential (inside-positive) indicating that its transport was electrogenic. Transport of CH3Hg.SG exhibited saturation kinetics with both high affinity (Km = 12 +/- 2 microM, Vmax = 0.23 +/- 0.02 nmol.mg-1.20 s-1) and low affinity (Km = 1.47 +/- 0.22 mM, Vmax = 1.23 +/- 0.14 nmol.mg-1.20 s-1) components. Uptake of this complex was inhibited by GSH, the GSH analog ophthalmic acid, S-methyl, S-ethyl, S-butyl, S-hexyl, S-octyl, and S-dinitrophenyl glutathione, but not by GSSG, bile acids, amino acids, and P-glycoprotein inhibitors. Furthermore, GSH competitively inhibited (Ki = 83 microM) and trans-stimulated CH3Hg.SG uptake into the canalicular vesicles. These studies provide the first kinetic characterization of a transport system for glutathione-mercaptides and indicate that CH3Hg.SG is not a substrate for the ATP-dependent, canalicular GSSG or glutathione S-conjugate carriers, but appears to be a substrate for canalicular carriers that also transport GSH. Because efflux systems for GSH are found in all mammalian cells, transport of glutathione-metal complexes by such carriers may be a common mechanism for the removal of methylmercury and possibly other metals from cells.
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PMID:Transport of the glutathione-methylmercury complex across liver canalicular membranes on reduced glutathione carriers. 814 67

We studied the potentiation of doxorubicin (DOX) activity in multidrug-resistant (MDR) cells by buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase, and by cepharanthine (CE), which interacts with P-glycoprotein. The glutathione (GSH) of MDR cells was approximately 1.5-fold greater than that of the parental cell line. BSO reduced GSH content of MDR cells compared to that of the sensitive ones. The BSO treatment (50 microM) enhanced the effect of DOX by 1.8-fold, while CE caused a greater reversal of drug resistance. The combination of BSO with CE produced further potentiation of DOX activity in an antiproliferative effect. Pretreatment of cells with BSO did not alter the cellular accumulation of DOX in the absence or presence of CE. The addition of BSO (30 mM) to the drinking water of mice reduced the tissue levels of GSH in tumor cells, suggesting that the marked decrease in GSH might diminish the ability of that tumor to resist DOX. Combined administration of CE and DOX resulted in enhancement of DOX antitumor activity and prolongation of survival time. The survival of mice treated with BSO and CE as a supplement to DOX treatment was superior that of mice receiving DOX alone. These studies demonstrated that the combinations of BSO with CE may be useful for killing drug-resistant tumor cells.
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PMID:Combined effects of buthionine sulfoximine and cepharanthine on cytotoxic activity of doxorubicin to multidrug-resistant cells. 855 53

The cytotoxicity of mitotic spindle poisons, vinca alkaloids and the anthracycline, adriamycin, against cisplatin-sensitive and -resistant rat lymphoma and human ovarian carcinoma cell lines was investigated. Interestingly, it was found that all cell lines were more sensitive to the mitotic spindle poisons, vincristine and vinblastine. Adriamycin was the least effective and taxol had intermediate activity. The Walker rat lymphoma cell line resistant to cisplatin (WR) exhibited the multiple drug resistance phenotype since it showed collateral resistance to all drugs (ranging from twofold to taxol, colcemid and colchicine and sixfold to the vinca alkaloids). Verapamil potentiated the cytotoxic activity of adriamycin and vincristine in a striking fashion with the Walker cells. P-glycoprotein was found to be present in the plasma membranes of the Walker cells with approximately a 2.5-fold increase in the WR as compared to the sensitive (WS) cells. Glutathione levels were elevated in all of the cisplatin-resistant cell lines when compared to the cisplatin-sensitive parental cell lines. A profound effect of buthionine sulfoximine pretreatment on adriamycin cytotoxicity was observed. Glutathione S-transferase (pi) was present in all the human cell lines but the WS cells had markedly lower levels (almost negligible) when compared to the WR cells. These observations imply that cisplatin-resistant cells may be more sensitive to mitotic spindle poisons and vinca alkaloids, irrespective of the mechanism of platinum resistance, and that the cytotoxicity of vinca alkaloids could be further modulated by verapamil, irrespective of the presence or absence of P-glycoprotein.
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PMID:Cross-resistance and collateral sensitivity to natural product drugs in cisplatin-sensitive and -resistant rat lymphoma and human ovarian carcinoma cells. 859 69

The role of the glutathione (GSH) system in vivo or in drug resistance has received much attention, since GSH is a major component of the cellular detoxification system. We Studied the effect of GSH depletion by buthionine sulfoximine (BSO), a potent inhibitor of gamma-glutamylcysteine synthetase, on doxorubicin (DOX) toxicity in mice. The administration of BSO (30 mM in drinking water for 5 days) significantly decreased the tissue GSH. The GSH depletion in various tissues by BSO was associated with a decrease in the detoxification of DOX in mice. A single dose of 20 mg/kg of DOX significantly reduced body weight and rectal temperature in mice 3 days after injection. The combination with BSO and cepharanthine (biscoclaurine alkaloid), a P-glycoprotein (P-gp) inhibitor, significantly potentiated decrease in body and hypothermia induced by DOX. The study demonstrates that BSO markedly increases the toxicological effect of DOX with the alterations in GSH of tissues and Suggests that the intracellular accumulation of DOX is not a factor.
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PMID:Effect of glutathione depletion by buthionine sulfoximine on doxorubicin toxicity in mice. 868 Aug 8


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