Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cultured human lung carcinoma cells (A549) were incubated in a calcium-free medium containing calcium chelators (EGTA, 1-10 mM or BAPTA, 5 mM) for 1 hour at 37 degrees C. With limited toxicity, the presence of calcium chelators resulted in a decrease of cellular GSH and detachment of the cells from the tissue culture flask. The permeable EGTA tetraacetoxymethyl ester (0.5mM-5 mM) caused a decrease in the cellular GSH content without cell detachment. GSH was not oxidized to GSSG nor formed mixed disulfides with protein thiols. AT-125, a gamma-glutamyl transpeptidase inhibitor, prevented detachment, but not the efflux of cellular GSH. Pretreatment with two impermeable compounds (ruthenium red, 100 microM and neomycin, 0.5-10 mM) protected the cells from detachment and prevented the decrease in intracellular GSH. The presence of calcium in the medium during the EGTA and BAPTA treatments also protected the cells. Calcium associated with the cytoplasmic membrane phospholipids or proteins appears important to limit membrane permeability for GSH efflux and to maintain cell attachment.
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PMID:Calcium chelation induced glutathione efflux from tumor cells and prevention by ruthenium red or neomycin. 170 44

Treatment of A549 human lung carcinoma cells with L-buthionine-[S,R]-sulfoximine (BSO) results concomitantly in cellular glutathione (GSH) depletion and growth inhibition. The nature of BSO effects on cell growth and the relationships between BSO inhibition of cell growth and BSO effects on cellular GSH levels were determined in this study. A dose dependent effect of BSO on cell growth was observed, but this effect was found not to correlate with BSO effects on cellular GSH levels. Treatment with BSO for 60 h at concentrations of 5 and 10 mM was found to deplete cellular GSH at similar rates and to an undetectable level (below 0.5 nmol/mg protein). However, cessation of growth occurred in 10 mM BSO whereas growth continued at better than one half the control rate in 5 mM BSO. The results suggest there may be a distinct threshold level of intracellular GSH (on the order of or less than 0.5 nmol/mg protein) required for cell growth and for cells to protect themselves from the antiproliferative effects of BSO. At a concentration of 10 mM, BSO inhibited both DNA and protein synthesis and arrested growth of A549 cells throughout rather than at a specific phase of the cell cycle. BSO inhibition of growth was not, as indicated by colony-forming efficiency (CFE) and electron microscopy studies, accompanied by indications of cytotoxic effects. A stimulatory effect of 0.1 mM BSO on the growth of A549 cells was found also.
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PMID:Buthionine sulfoximine induced growth inhibition in human lung carcinoma cells does not correlate with glutathione depletion. 193 16

Human lung carcinoma A549-T27 cells were used to determine the effect of diamide on cadmium accumulation. Treatment of the cells with diamide decreased their cellular glutathione content to 51.6 +/- 7% of control and significantly decreased their cadmium accumulation both as a function of time and as a function of Cd2+ concentration. Verapamil also decreased cadmium accumulation. Its effect compares well in magnitude with that which resulted from diamide treatment. No additive effect was observed when the cells were simultaneously treated with diamide and verapamil. The results suggest that a change in the GSH/GSSG ratio affects cadmium uptake. Further, calcium channels may be involved in cadmium uptake by A549-T27 cells in a fashion that is dependent on sulfhydryl status.
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PMID:Diamide reduces cadmium accumulation by human lung carcinoma A549 cells. 216 Jul 46

The activity of the thiol-dependent enzyme glyceraldehyde-3-phosphate dehydrogenase (GPD), in vertebrate cells, was modulated by a change in the intracellular thiol:disulfide redox status. Human lung carcinoma cells (A549) were incubated with 1-120 mM H2O2, 1-120 mM t-butyl hydroperoxide, 1-6 mM ethacrynic acid, or 0.1-10 mM N-ethylmaleimide for 5 min. Loss of reduced protein thiols, as measured by binding of the thiol reagent iodoacetic acid to GPD, and loss of GPD enzymatic activity occurred in a dose-dependent manner. Incubation of the cells, following oxidative treatment, in saline for 30 min or with 20 mM dithiothreitol (DTT) partially reversed both changes in GPD. The enzymatic recovery of GPD activity was observed either without addition of thiols to the medium or by incubation of a sonicated cell mixture with 2 mM cysteine, cystine, cysteamine, or glutathione (GSH); GSSG had no effect. Treatment of cells with buthionine sulfoximine (BSO) to decrease cellular GSH by varying amounts caused a dose-related increase in sensitivity of GPD activity to inactivation by H2O2 and decreased cellular ability for subsequent recovery. GPD responded in a similar fashion with oxidative treatment of another lung carcinoma cell line (A427) as well as normal lung tissue from human and rat. These findings indicate that the cellular thiol redox status can be important in determining GPD enzymatic activity.
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PMID:Cellular recovery of glyceraldehyde-3-phosphate dehydrogenase activity and thiol status after exposure to hydroperoxides. 229 24

The relationship between glutathione content and cell growth was investigated in A549 human lung carcinoma cells. A decreased cellular glutathione content was achieved by exposing the cells to L-buthionine-SR-sulfoximine (BSO). It also occurred in these cells as they approached their plateau phase of growth. During exponential growth, a lower initial glutathione content correlated with a longer lag phase in subcultured cells. Further, depletion of cellular glutathione by BSO inhibited cell growth. This inhibition became apparent 36 h after the addition of BSO. These observations raise the possibility that a critical concentration of GSH may be required for optimal growth of A549 human lung carcinoma cells.
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PMID:Glutathione content and growth in A549 human lung carcinoma cells. 229 58

Subpopulations T20 and T27, cloned from the human lung carcinoma line A549, differ significantly in their Cd2+ cytotoxic response. T27 has an LC50 of 31 microM Cd2+ and a cytotoxic response threshold of 5 microM Cd2+, whereas the T20s LC50 is 15 microM Cd2+ and there is no observed threshold for cytotoxicity. Cadmium-induced metallothionein (MT) synthesis, cadmium accumulation, glutathione (GSH) content, and Cd2(+)-induced changes in GSH content were studied in T20 and T27 in an attempt to determine the mechanism(s) causing differential cytotoxic response. MT synthesis measured by following Cd2(+)-induced [35S] incorporation into MT was found not to differ between T20 and T27. There is, however, a difference in Cd2+ accumulation between the two subclones. T20 and T27 cells were exposed to 5 microM Cd2+ for different times or to different concentrations of Cd2+ for 8 h. The T27 subline, which is the more Cd2+ resistant, was found to accumulate significantly more Cd2(+)-both as a function of time exposed to Cd2+ and as a function of Cd2+ concentration. The two subpopulations were found to have comparable initial GSH contents, but showed different Cd2(+)-induced changes in [GSH] when the cells were exposed to 5 microM Cd2+. T27 cells maintained their GSH content following Cd2+ exposure but T20 cells showed a Cd2(+)-induced decrease in GSH content. The results indicate that the difference in Cd2+ cytotoxic response between A549--T20 and A549--T27 cells is not attributable to alterations in MT synthesis nor to a difference in initial GSH content. Relative Cd2+ cytotoxicity also does not in these cells correlate with relative Cd2+ accumulation. The fact that T27 cells accumulate more Cd2+ and yet are more Cd2+ resistant than T20 cells suggests that T27 cells have a much more effective non-MT mechanism to handle intracellular Cd2+. This may involve different GSH metabolism and/or yet undefined molecular factors.
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PMID:Cellular cadmium responses in subpopulations T20 and T27 of human lung carcinoma A549 cells. 232 Dec 46

The role of glutathione (GSH) in resistance to cisplatin (CDDP) was studied in a human small cell lung carcinoma cell line (GLC4) and a CDDP-resistant subline (GLC4-CDDP). In addition to studying the steady state of GSH, the kinetics of this defence system were also studied via the monitoring of the GSH status of the cells under continuous pressure of CDDP. GLC4-CDDP maintained its elevated GSH level whereas GLC4 (under pressure of CDDP) quickly synthesised GSH to about twice its initial level, corresponding with 80% of the GSH level of GLC4-CDDP. D,L-buthionine-S,R-sulphoximine (BSO) was used to analyse the role of GSH in resistance to CDDP. Pretreatment with BSO (48 h, 50 microM, GSH not detectable) increased the CDDP-induced cytotoxicity 2.8-fold in GLC4-CDDP and 1.7-fold in GLC4. In GLC4 no changes in the amount of platinum (Pt) bound to DNA could be observed after GSH depletion. Changes in formation of interstrand cross-links or the main Pt-containing intrastrand cross-link in digested DNA, the Pt-GG adduct, were also not observed. In GSH depleted GLC4-CDDP cells, an increase in the amount of Pt bound to DNA and in the Pt-GG adduct was observed. Pretreatment with BSO substantially reduced the repair of Pt bound to DNA in both cell lines. We conclude that an increased GSH level and GSH synthesis capacity were demonstrated in CDDP resistant cells. The observations after BSO treatment suggest two roles for GSH in CDDP resistance, namely that of a cytosolic elimination resulting in less DNA platination and a nuclear effect on the formation and repair of DNA platinum adducts.
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PMID:The role of glutathione in resistance to cisplatin in a human small cell lung cancer cell line. 239 Apr 86

Glutathione (GSH) depletion sensitizes human lung carcinoma (A549-T27) cells to the cytotoxic effects of Cd++. The effects of GSH depletion on Cd++ accumulation and Cd++-induced metallothionein (MT) content were investigated to determine the possible role of these Cd++ responses in the sensitization process. Cellular GSH was depleted to 20% to 25% of control levels with buthionine sulfoximine (BSO), or diethyl maleate (DEM), respectively. Neither treatment significantly affected Cd++-induced accumulation of exogenous 35s-cysteine into intracellular MT in a dose-dependent fashion. The results indicate that neither enhanced Cd++ accumulation nor reduced MT synthesis plays a primary role in affecting enhanced Cd++ cytotoxicity in A549 cells with reduced GSH levels. Although BSO inhibition of GSH synthesis enhanced MT synthesis, it sensitized the cells to Cd++, which suggests an additive effect of GSH and MT in cadmium cytoprotection. This observation also raises the possibility that intracellular cysteine levels limit Cd++-induced MT accumulation rates.
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PMID:Enhanced cadmium cytotoxicity in A549 cells with reduced glutathione levels is due to neither enhanced cadmium accumulation nor reduced metallothionein synthesis. 259 84

Glutathione S-transferase (GST) is a family of multimolecular forms with multi-functions for detoxication of drugs, and certain GST forms have been reported to concern multidrug resistance (MDR) mechanisms of neoplastic cells to anticancer drugs. In this paper, recent studies of GSTs concerning MDR are briefly reviewed, and the problems to be clarified are discussed. The reduced glutathione (GSH) is known to play important roles in the inactivation (detoxication) of the anticancer drugs. Most of them, especially alkylating agents, are conjugated with GSH by GSTs and detoxified, and the peroxides from drugs such as adriamycin are also reduced with GSH and detoxified by the GSH peroxidase activity of certain GST forms. Rat GST-P (GST 7-7) and human GST-pi, both of which belong to Class pi in the species-independent classification of GST, have been known as a marker enzyme for rat and human (pre) neoplastic lesions, respectively. GST-P is increased in rat hepatic preneoplastic foci resistant to cytotoxic agents. GST-pi is also increased not only in cancer cells such as colon carcinoma and non-small cell lung carcinoma, which exhibit "natural resistance" to anticancer drugs, but also increased in breast, ovarian and other tissue carcinomas with increased "acquired resistance" to certain drugs. A few research groups have attempted to confirm by transfection of a vector expressing a GST form such as GST-pi into non-resistant cell lines whether there is a direct relationship between the expression of a specific GST form and the appearance of MDR. However, MDR did not always appear. Recently, it was found in our laboratory that GST-P, GST-pi and even mouse GST II in Class pi, all are very strongly inactivated by SH-modifiers and active oxygens, indicating that these properties may be useful for overcoming MDR, if the forms really are involved with MDR.
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PMID:[Anti-cancer drug resistance and glutathione S-transferases]. 265 Jun 31

Eupatoriopicrin (EUP), a sesquiterpene lactone from Eupatorium cannabinum L., possesses cytostatic activity. This was demonstrated for FIO 26 cells in vitro with the aid of a clonogenic assay and in vivo by tumour growth delay in FIO 26 and Lewis lung tumour-bearing mice. In vitro the IC50 for 1 h exposure to EUP was 1.5 microgram ml-1 (4.1 nmol ml-1). This concentration depleted about 25% of its cellular GSH concentration. Pretreatment of FIO 26 cells with BSO, resulting in greater than 99%. GSH depletion, enhanced the cytotoxic effect of EUP. The dose-enhancement factor at the level of 10% cell survival was 2.3. Growth inhibition of the Lewis lung carcinoma and the FIO 26 fibrosarcoma, solidly growing in C57Bl mice, was found after i.v. injection of 20 or 40 mg kg-1 EUP, at a tumour volume of about 500 microliters. Pretreatment with BSO at a dose of 4 mmol kg-1 i.p., 6 h before EUP administration, resulted in a significantly stronger growth delay of both tumours compared with EUP only. At the time of EUP treatment, cellular GSH in the tumours was reduced by BSO treatment to about 60%. It is concluded that EUP possesses antitumour activity in vivo and that chemosensitisation of EUP may be accomplished by pretreatment with BSO, indicating that endogenous GSH protects against the cytostatic action of EUP.
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PMID:Enhanced cytostatic activity of the sesquiterpene lactone eupatoriopicrin by glutathione depletion. 275 25


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