Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1260386 (GSH)
 38,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The multidrug resistant cell lines HL60/AR and GLC4/ADR show high overexpression of the gene encoding the multidrug resistance associated protein MRP compared to their drug sensitive parental counterparts. This and the virtual absence of mdr1/P-glycoprotein gene expression was proven by a complementary DNA polymerase chain reaction (cDNA-PCR) approach. Applying a 72-hour tetrazolium based colorimetric MTT-assay we demonstrate on both MDR sublines a dose-dependent modulation of drug resistances by the leukotriene LTD4 receptor antagonist MK571. A complete reversal of vincristine resistances was achieved at final MK571 concentrations of 30 microM (HL60/AR) or 50 microM (GLC4/ADR) which by itself did not disturb cellular proliferation. The drug resistance of a mdr1/P-gp overexpressing multidrug-resistant HL60 subline, in contrast, was not significantly affected by MK571. Similar effects were seen using the glutathione (GSH) synthesis inhibitor buthionine sulfoximine (BSO). Our results point to a relationship between MRP and a conjugate transporter and identify MK571 as a new tool structure for developing modulators specific for a MRP associated multidrug resistance.
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PMID:The leukotriene LTD4 receptor antagonist MK571 specifically modulates MRP associated multidrug resistance. 788 49

We have reported the establishment of a mitomycin-C (MMC)-resistant non-small-cell lung-cancer cell line, PC-9/MC4. As determined by an MTT assay, this resistant cell line was found to be 4 times more sensitive to adriamycin (ADM) than was the parental PC-9. There were no significant differences in sensitivity to etoposide, mitoxantrone, daunomycin, epirubicin, pirarubicin, 9-aminoanthracycline or 3'-deamino-3'-morpholino-13-deoxo-10-hydroxy carminomycin. These data suggest that neither qualitative or quantitative changes in DNA topoisomerase II nor the enhanced repair of DNA can explain the differing sensitivity to ADM observed. No significant differences were found in the accumulation of ADM and glutathione (GSH) in these cell lines. Although total glutathione-S-transferase (GST) activity in PC-9/MC4 cells was lower than that observed in PC-9 cells and treatment with ethacrynic acid (EA) reduced sensitivity to ADM in both cell lines, relative resistance was unaffected. NADH-cytochrome b5 reductase (B5R) activity in PC-9/MC4 cells showed a 3-fold greater decrease than that in PC-9 cells, and DT-diaphorase (DTD) activity in PC-9/MC4 cells showed an approximately 200-fold greater decrease than that in PC-9 cells. Addition of dicumarol, an inhibitor of DTD, decreased the sensitivity of ADM of PC-9 but not of PC-9/MC4. DTD activity in the PC-9 cell line was inhibited by treatment with dicumarol while in PC-9/MC4 it remained unchanged. These data suggest that DT-diaphorase is a determinant of sensitivity to ADM in the 2 cell lines.
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PMID:DT-diaphorase as a determinant of sensitivity to adriamycin in non-small-cell lung-cancer cell lines. 792 20

The role of glutathione (GSH) and protein thiols in the pathobiochemical process of CBrCl3 cytotoxicity was investigated in isolated hepatocytes. Administration of 0.5, 1.0 and 1.5 mmol/l CBrCl3 affected cellular viability as assessed by trypan blue exclusion, release of lactate dehydrogenase and loss of intracellular potassium in a dose-dependent manner. Intracellular glutathione and the capacity to reduce 3-(4,5-dimethylthiazolyl-2-)-2,5-diphenyltetrazolium bromide (MTT, thiazolyl blue) decreased almost independently of the CBrCl3 concentration. Protein thiols were not markedly oxidized in the presence of CBrCl3. However, compromising cellular defence mechanisms by either inhibition of glutathione regeneration or depletion of glutathione enhanced the cytotoxicity of CBrCl3 and induced a loss of protein thiols in the late phase of cellular injury. Under these conditions the thiol-dependent Na+,K+ATPase revealed high sensitivity towards CBrCl3. Thus, glutathione proved to exert effective cytoprotection, and sulfhydryl groups of particular proteins were supposed to be an important target of radical attack.
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PMID:The role of glutathione and protein thiols in CBrCl3-induced cytotoxicity in isolated rat hepatocytes. 797 37

Lymphoblasts were separated from the peripheral blood or bone marrow of 19 children (age 1-15, median 4 years) and 13 adults (age 18-59, median 47 years) with acute lymphoblastic leukaemia (ALL). Twenty-one samples were examined at presentation (16 from children and five from adults) and 13 at relapse (three children and ten adults). Glutathione (GSH) levels in leukaemic blasts were compared with in vitro sensitivity to a variety of cytotoxic drugs assessed using 3-(4-5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) as an indicator of cell viability. There was a statistically significant positive correlation between GSH levels and in vitro sensitivity to daunorubicin (Spearman's rank correlation coefficient rs = 0.38, p < 0.04), melphalan (rs = 0.39, p < 0.04) and prednisolone (rs = 0.48, p < 0.01), but not mitozantrone, etoposide or 6-thioguanine. There was no statistically significant difference in median GSH levels between blasts from children and adults or between samples taken at presentation or relapse. The sample median GSH levels in blasts from patients who responded to therapy (n = 21) and those who did not (n = 7) were 1.05 fmol/cell (97.3% confidence interval (CI) 0.78-1.52) and 2.66 fmol/cell (98.4% CI 0.53-5) respectively, and this difference was statistically significant (p < 0.02, Mann-Whitney U test). In two patients for whom paired samples were available, GSH levels in blasts on relapse were greater than 2-fold higher than on presentation. These results provide evidence that elevation of GSH in leukaemic blasts may be associated with resistance to drugs used in the treatment of children and adults with ALL.
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PMID:Raised intracellular glutathione levels correlate with in vitro resistance to cytotoxic drugs in leukaemic cells from patients with acute lymphoblastic leukemia. 809 28

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

Human cervical carcinoma HeLa cells were made resistant to cisplatin by one of two schedules; "acute" (cells repeatedly treated with cisplatin for 1 h in serum-free medium--CA cells) or "continuous" (cells treated repeatedly for 24 h in complete medium--CK cells). The sensitivity of CA and CK sublines to cisplatin and various other antineoplastic drugs was determined by the modified MTT staining procedure. The possible involvement of glutathione (GSH), glutathione S-transferases (GST) and metallothioneins (MT) in cisplatin resistance was examined. The results show that acutely treated CA cells became more resistant to cisplatin than CK cells. The resistance to cisplatin does not involve either glutathione or glutathione transferase. The increased levels of metallothioneins might be involved in the development of resistance. The sensitivity of CA and CK sublines to the selected drugs was different from that of the parent cells. Both sublines became cross-resistant to vincristine and methotrexate, but only CA cells exhibited cross resistance to etoposide doxorubicin and 5-fluorouracil. Thus, the development of resistance to cisplatin is a consequence of numerous intracellular alterations that are reflected in cell response to a variety of anticancer drugs. The response depends on the schedule of resistance development and on the nature of the secondary agent.
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PMID:The characterization of two human cervical carcinoma HeLa sublines resistant to cisplatin. 812 44

The pathophysiology of hepatic veno-occlusive disease is poorly understood. These studies were undertaken to determine the initial cellular target and the role of glutathione detoxification of dacarbazine, a toxin implicated in hepatic veno-occlusive disease. Sinusoidal endothelial cells (SECs) and hepatocytes were isolated and plated in culture dishes. Dacarbazine (5-(3,3-dimethyl-triazeno) imidazole-4-carboxamide), 3 and 6 mM, was toxic to SECs but not to hepatocytes. Onset of toxicity occurred between 11 and 12 hr as determined by serial MTT assays and ethidium homodimer dye exclusion. Glutathione detoxification of dacarbazine in SECs was suggested by: (1) depletion of glutathione before onset of toxicity; (2) exacerbation of toxicity by buthionine sulfoximine (BSO) depletion of glutathione; and (3) protection by exogenous glutathione. Protection by exogenous glutathione may be by uptake of intact tripeptide rather than by extracellular hydrolysis: neither acivicin (inhibitor of gamma-glutamyltranspeptidase) nor BSO (inhibitor of gamma-glutamylcysteine synthetase) blocked the protective effect, and glutathione disulfide did not protect. The relative resistance to dacarbazine toxicity seen in hepatocytes is not due to more efficient GSH detoxification, because toxicity was not unmasked in hepatocytes cultures in medium lacking sulfur amino acid precursors of GSH. In conclusion, glutathione status may play an important role in the susceptibility to toxicity. Furthermore, the findings suggest that the SEC is the initial in vivo target of dacarbazine due to a relatively higher level of metabolic activation that more readily overcomes the available detoxification.
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PMID:Dacarbazine toxicity in murine liver cells: a model of hepatic endothelial injury and glutathione defense. 813 39

Ajoene (4,5,9-trithiadodeca-1,6,11-triene-9-oxide), a garlic-derived natural compound, which had been shown to have cytostatic/cytotoxic properties, was tested with a B cell lymphoma-derived cell line (BJA-B cells) in order to elucidate its mechanism of cytotoxic action. Viability of the cells was determined by the Trypan blue exclusion test and the colorimetric tetrazolium (MTT) assay, whereas metabolic disturbance was evaluated by measuring the pools of reduced (GSH), oxidized glutathione (GSSG) and the acidic amino acids, Glu and Asp. Fast uptake of ajoene was accompanied by an immediate reduction of the GSH and increase in the GSSG levels. The extent of these changes, as well as the further development of the metabolite pools, depended on the ajoene dose per cell. At a sublethal ajoene dose the GSH and GSSG pools rose at the later stages to levels much higher than in the control experiment. Bleb formation at the cytoplasmic membrane was a further rapid phenomenon, although injuries detected by Trypan blue exclusion developed only at a later stage. The MTT assay, performed in a parallel experiment (48 h after ajoene addition), showed, however, that reduction of cell viability was established at the very beginning of ajoene exposure. Altogether, the action of ajoene strongly resembled oxidative stress (i.e., interference with SH homeostasis and its pleiotropic consequences to cell physiology and metabolism.
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PMID:Injuries to cultivated BJA-B cells by ajoene, a garlic-derived natural compound: cell viability, glutathione metabolism, and pools of acidic amino acids. 826 28

Prostate cancer that is androgen-insensitive is unresponsive to a wide spectrum of cytotoxic agents, including all of the alkylating agents. Since a major pathway for the detoxification of the alkylating agents is conjugation with glutathione (GSH), GSH depletion has proved to be effective as a technique to restore melphalan sensitivity in melphalan-resistant cancer cell lines. However, the effect of GSH depletion has not been widely studied in tumor cell lines that have not developed resistance due to previous exposure to alkylating agents. Thus, we decided to investigate GSH depletion as a technique to increase melphalan cytotoxicity to PC-3 cells, an androgen-insensitive prostate cancer line. After 2 and 6 h incubation with 0.25-5 microM melphalan, virtually no effect was observed on either clonogenic lethality or MTT viability until 5 microM exposures. A 24-h incubation of the cells with 100 microM buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, reduced the GSH content by 70%-75%. Following GSH depletion, an increase in clonogenic lethality and a decrease in MTT viability occurred after exposure to concentrations as low as 0.25 microM. The dose modification factor ranged from 2.9 after 2 h incubation to 4.5 at 6 h. These results provide support for additional studies in prostate cancer for further investigation of GSH depletion as a technique to induce sensitivity to alkylating agents in this chemotherapy-resistant tumor.
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PMID:Glutathione depletion increases the cytotoxicity of melphalan to PC-3, an androgen-insensitive prostate cancer cell line. 846 27

Inclusion complexes of gamma-cyclodextrin and octamethylcyclotetrasiloxane (D4), decamethyltetrasiloxane (M10TS), and 1,3,5,7-tetramethyltetravinylcyclotetra - siloxane (TMTV-D4) were prepared to compare the cytotoxic effects of siloxanes in vitro. In these preparations, the hydrophobic siloxanes are surrounded by a hydrophilic shell of eight circularly linked D-glucose molecules (gamma-cyclodextrin), and upon contact with plasma membranes the siloxane molecule can intercalate into the lipid bilayer of the cell membrane. XRPC24, 2-11 plasmacytoma, CH12.LX lymphoma and P388D1 macrophage-like cells were used as indicator cells in toxicity assays. Using an MTT tetrazolium reduction to formazan test, a colorimetric method to determine the number of viable cells, the 50% minimal lethal doses (CD50) for the siloxane compounds were found to range from 30 to 50 microM. Sublethal doses (e.g., 15 microM and lower) resulted in the loss of lactate dehydrogenase (LDH) and glutathione (GSH) from the cytosolic compartment of the target cells and thus indicated cytotoxicity. Treatment of macrophages with siloxanes resulted in a higher production of interleukin-6 (IL-6) than was exhibited by untreated macrophages. The B9 cell bioassay of these treated cells showed as much as a 10 fold higher production (500 U/ml) of IL-6 than did the untreated cells. The degree of increase was dependent on the compound and concentration used. The results of this study show that low molecular weight siloxanes produce lethal effects on B-lymphocyte derived target cells in vitro and permeabilize the plasma membranes at lower sublethal concentrations.
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PMID:Cytotoxicity and membrane damage in vitro by inclusion complexes between gamma-cyclodextrin and siloxanes. 856 93


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