Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reduced glutathione or simply glutathione (gamma-glutamylcysteinylglycine; GSH) is found in the cytosol of most cells of the body. GSH in the epithelial lining fluid (ELF) of the lower respiratory tract is thought to be the first line of defense against oxidative stress. Inhalation (nebulized or aerosolized) is the only known method that increases GSH's levels in the ELF. A review of the literature was conducted to examine the clinical effectiveness of inhaled GSH as a treatment for various pulmonary diseases and respiratory-related conditions. This report also discusses clinical and theoretical indications for GSH inhalation, potential concerns with this treatment, its presumed mechanisms of action, optimal doses to be administered and other important details. Reasons for inhaled GSH's effectiveness include its role as a potent antioxidant, and possibly improved oxygenation and host defenses. Theoretical uses of this treatment include Farmer's lung, pre- and postexercise, multiple chemical sensitivity disorder and cigarette smoking. GSH inhalation should not be used as a treatment for primary lung cancer. Testing for sulfites in the urine is recommended prior to GSH inhalation. Minor side effects such as transient coughing and an unpleasant odor are common with this treatment. Major side effects such as bronchoconstriction have only occurred among asthma patients presumed to be sulfite-sensitive. The potential applications of inhaled GSH are numerous when one considers just how many pulmonary diseases and respiratory-related conditions are affected by deficient antioxidant status or an over production of oxidants, poor oxygenation and/or impaired host defenses. More studies are clearly warranted.
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PMID:The treatment of pulmonary diseases and respiratory-related conditions with inhaled (nebulized or aerosolized) glutathione. 1831 45

Cadmium is a nonessential toxic metal in mammals. Its toxicity is mainly caused by interactions with cellular proteins that result in protein dysfunction and then disturb normal cellular functions. Glutathione (GSH) has been reported to play a role in cadmium resistance by serving as a cofactor for multidrug resistance protein 1/GS-X pump-mediated cadmium elimination. To further investigate the role of GSH in cadmium toxicity, we carried out a comparative study using small-cell lung cancer-derived cell lines, SR3A, and those that were stably transfected with glutamate cysteine ligase catalytic subunit (GCLC), a rate-limiting enzyme in GSH biosynthesis. These GCLC stably transfected cell lines produced higher levels of GSH and were more resistant to cadmium toxicity than the parental cell line was. The rates of cadmium uptake were reduced in these GCLC-transfected cell lines, which were associated with down-regulation of the cadmium transporter ZIP8/SLC39A8. Further analyses demonstrated that Sp1 binding site at the proximal promoter region of ZIP8 was sensitive to the GSH level and that the expression level of transcription factor Sp1 was reduced by increased GSH levels. We also demonstrated that low concentrations of cadmium exposure down-regulated ZIP8 expression with concomitant reduction of Sp1 expression. Taken together, these results demonstrate the importance of Sp1 in the regulation of ZIP8 expression. More important, our results reveal a new mechanism by which elevated GSH levels confer cadmium resistance by down-regulation of ZIP8 expression through the suppression of Sp1.
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PMID:Elevated GSH level increases cadmium resistance through down-regulation of Sp1-dependent expression of the cadmium transporter ZIP8. 1855 57

Carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) is an uncoupler of mitochondrial oxidative phosphorylation in eukaryotic cells. Here, we investigated an involvement of O(2)(*-) and GSH in FCCP-induced Calu-6 cell death and examined whether ROS scavengers rescue cells from FCCP-induced cell death. Levels of intracellular O(2)(*-) were markedly increased depending on the concentrations (5-100 microM) of FCCP. A depletion of intracellular GSH content was also observed after exposing cells to FCCP. Stable SOD mimetics, Tempol and Tiron did not change the levels of intracellular O(2)(*-), apoptosis and the loss of mitochondrial membrane potential (DeltaPsi(m)). Treatment with thiol antioxidants, NAC and DTT, showed the recovery of GSH depletion and the reduction of O(2)(*-) levels in FCCP-treated cells, which were accompanied by the inhibition of apoptosis. In contrast, BSO, a well-known inhibitor of GSH synthesis, aggravated GSH depletion, oxidative stress of O(2)(*-) and cell death in FCCP-treated cells. Taken together, our data suggested that FCCP as an O(2)(*-) generator, induces apoptosis via the depletion of intracellular GSH contents in Calu-6 cells.
Lung Cancer 2009 Feb
PMID:Carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) as an O2(*-) generator induces apoptosis via the depletion of intracellular GSH contents in Calu-6 cells. 1858 19

Arsenic trioxide (ATO) affects many biological processes such as cell proliferation, apoptosis, differentiation and angiogenesis. L-buthionine sulfoximine (BSO) is an inhibitor of GSH synthesis. We tested whether ATO reduced the viability of lung cancer A549 cells in vitro, and investigated the in vitro effect of the combination of ATO and BSO on cell viability in relation to apoptosis and the cell cycle. ATO caused a dose-dependant decrease of viability of A549 cells with an IC50 of more than 50 microM. Low doses of ATO or BSO (1 approximately 10 microM) alone did not induce cell death. However, combined treatment depleted GSH content and induced apoptosis, loss of mitochondrial transmembrane potential (DeltaPsi(m)) and cell cycle arrest in G2. Reactive oxygen species (ROS) increased or decreased depending on the concentration of ATO. In addition, BSO generally increased ROS in ATO-treated A549 cells. ROS levels were at least in part related to apoptosis in cells treated with ATO and/or BSO. In conclusion, we have demonstrated that A549 lung cells are very resistant to ATO, and that BSO synergizes with clinically achievable concentration of ATO. Our results suggest that combination treatment with ATO and BSO may be useful for treating lung cancer.
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PMID:Induction of apoptosis in arsenic trioxide-treated lung cancer A549 cells by buthionine sulfoximine. 1859 14

Chemoprevention is regarded as one of the most promising and realistic approaches in the prevention of cancer. Several bioactive compounds present in fruits and vegetables have revealed their cancer curative potential on lung cancer. Hesperidin is one such naturally occurring flavonoid widely found in citrus fruits. The aim of the present study is to divulge the chemopreventive nature of hesperidin during benzo(a)pyrene (B(a)P) induced lung cancer in Swiss albino mice. Administration of B(a)P (50 mg/kg body weight) to mice resulted in increased lipid peroxides (LPO), lung specific tumor marker carcinoembryonic antigen (CEA) and serum marker enzymes aryl hydrocarbon hydroxylase (AHH), gamma glutamyl transpeptidase (GGT), 5'nucleotidase (5'ND) and lactate dehydrogenase (LDH) with concomitant decrease in the levels of tissue antioxidants like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), vitamin E and vitamin C. Hesperidin supplementation (25 mg/kg body weight) significantly attenuated these alterations thereby showing potent anticancer effect in lung cancer. Further the antiproliferative effect of hesperidin was confirmed by histopathological analysis and proliferating cell nuclear antigen (PCNA) immunostaining. Overall, these findings substantiate the chemopreventive potential of hesperidin against chemically induced lung cancer in mice.
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PMID:Antioxidant and anticancer efficacy of hesperidin in benzo(a)pyrene induced lung carcinogenesis in mice. 1870 64

Antimycin A (AMA) inhibits the mitochondrial electron transport between cytochromes b and c. However, the relationship between AMA and lung cancer cells is poorly understood. In this study, we investigated the involvement of reactive oxygen species (ROS) and glutathione (GSH) in AMA-treated lung cancer Calu-6 cell death. Treatment with AMA reduced cell viability in a dose-dependent manner for 72 h. The intracellular ROS levels were decreased in Calu-6 cells treated with low doses of AMA (10, 25 or 50 microM) at 72 h. However, the levels increased in cells treated with a high dose of 100 microM AMA. Levels of O2.- were significantly increased in AMA-treated cells at 72 h. The increases in ROS levels including O2.- in AMA-treated cells were observed within 10 min. Treatment with AMA reduced the intracellular GSH content. SOD activity was up-regulated in AMA-treated Calu-6 cells at 72 h. However, catalase activity was down-regulated by AMA. Treatment with tiron, a ROS scavenger, reduced the intracellular ROS levels, which were associated with a partial reduction of apoptosis. Treatment with exogenous SOD and catalase significantly inhibited loss of the mitochondrial transmembrane potential (DeltaPsim) in AMA-treated Calu-6 cells. In conclusion, our results suggest that the changes of intracellular ROS and GSH affect apoptosis in AMA-treated Calu-6 cells.
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PMID:Tiron, a ROS scavenger, protects human lung cancer Calu-6 cells against antimycin A-induced cell death. 1908 70

High levels of benzo(a)pyrene diol epoxide (BPDE)-DNA adducts in white blood cells have been indicated as a risk factor for lung cancer. Sensitive, specific, fast and cost-efficient techniques for the detection of BPDE-DNA adducts in white blood cells are required for routine human biomonitoring. In the present study, an immunoassay based on CE/LIF was developed for the detection of BPDE-DNA adducts in mononuclear white blood cells (MNCs). Although glutathione (GSH) conjugation catalyzed by glutathione-S-transferase (GST) is considered to be the major pathway for inactivating BPDE, the effect of GSH depletion on BPDE-DNA adduct formation in MNCs has not been assessed. Therefore, we applied the newly developed method to study the effect of GSH depletion by D,L-buthionine-[S,R]-sulfoximine (BSO) on the level of DNA adducts. We found that pretreatment of MNCs with 150 microM BSO for 2 h prior to BPDE exposure increased the level of BPDE-DNA adducts appreciably (by approximately 70%). Further investigations revealed that the 2-h BSO treatment neither decreased the GSH level instantly nor affected GST activity; rather, it prevented the induction of GSH in response to subsequent BPDE incubation. The blocked synthesis of GSH might be responsible for the elevated level of BPDE-DNA adducts in MNCs after BSO and BPDE treatment.
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PMID:Detection of benzo(a)pyrene diol epoxide-DNA adducts in mononuclear white blood cells by CE immunoassay and its application to studying the effect of glutathione depletion. 1934 25

Carotenoids are widely used as important micronutrients in food. Furthermore, carotenoid supplementation has been used in the treatment of diseases associated with oxidative stress such as various types of cancer, inflammatory diseases or cystic fibrosis. However, in some clinical studies harmful effects have been observed, e.g. a higher incidence of lung cancer in individuals exposed to extraordinary oxidative stress. The causal mechanisms of harmful effects are still unclear. Carotenoid breakdown products (CBPs) including highly reactive aldehydes and epoxides are formed during oxidative attacks in the course of antioxidative action. We investigated the formation of CBPs by stimulated neutrophils (and at further conditions), tested the hypothesis that CBPs may exert mitochondriotoxicity and tried to prevent toxicity in the presence of members of the antioxidative network. Stimulated neutrophils are able to degrade beta-carotene and to generate a number of CBPs. Concerning mitochondriotoxicity, we found that CBPs strongly inhibit state 3 respiration of rat liver mitochondria at concentrations between 0.5 and 20 microM. This was true for retinal, beta-ionone, and for mixtures of cleavage/breakdown products. The inhibition of mitochondrial respiration was accompanied by a reduction in protein sulfhydryl content, decreasing GSH levels and redox state, and elevated accumulation of malondialdehyde. Changes in mitochondrial membrane potential favor functional deterioration in the adenine nucleotide translocator as a sensitive target. The presence of additional antioxidants such as alpha-tocopherol, ascorbic acid, N-acetyl-cysteine or others could mitigate mitochondriotoxicity. The findings reflect a basic mechanism of increasing the risk of cancer induced by carotenoid degradation products.
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PMID:Beta-carotene degradation products - formation, toxicity and prevention of toxicity. 1936 12

Antimycin A (AMA) inhibits mitochondrial electron transport between cytochrome b and c. We recently demonstrated that AMA inhibits the growth of lung cancer Calu-6 cells and the changes of reactive oxygen species (ROS) and glutathione (GSH) levels affect apoptosis in Calu-6 cells. Here, we examined the effects of N-acetyl-cysteine (NAC, a well known antioxidant), L-buthionine sulfoximine (BSO, an inhibitor of GSH synthesis), diethyl-dithiocarbamate (DDC, an inhibitor of Cu, Zn-SOD) or 3-amino-1,2,4-triazole (AT, an inhibitor of catalase) on AMA-treated Calu-6 cells in relation to cell death, ROS and GSH levels. Treatment with AMA induced cell growth inhibition, apoptosis and the loss of mitochondrial membrane potential (MMP) (DeltaPsim) in Calu-6 cells. While the intracellular ROS level was decreased in 50 microM AMA-treated Calu-6 cells, O2.- levels among ROS were significantly increased. AMA also induced GSH depletion in Calu-6 cells. Treatment with NAC showed decreasing effect on O2.- levels in AMA-treated cells preventing apoptosis, MMP (DeltaPsim) loss and GSH depletion in these cells. BSO significantly increased GSH depletion and apoptosis in AMA-treated cells. While both DDC and AT increased ROS levels in AMA-treated Calu-6 cells, only DDC intensified GSH depletion and apoptosis. BSO and AT increased the ROS level in Calu-6 control cells, but these agents did not induce apoptosis and GSH depletion. In conclusion, our results suggest that GSH depletion rather than ROS level in AMA-treated Calu-6 cells is more tightly related to apoptosis.
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PMID:The effects of N-acetyl cysteine, buthionine sulfoximine, diethyldithiocarbamate or 3-amino-1,2,4-triazole on antimycin A-treated Calu-6 lung cells in relation to cell growth, reactive oxygen species and glutathione. 1957 81

Glutathione S-transferases (GSTs) M1 and T1 are known to be polymorphic in humans. Both polymorphisms are due to gene deletions which are responsible for the existence of null genotypes. Previous studies have suggested that GST genotypes may play a role in determining susceptibility to a number of unrelated cancers, including lung cancer. The GSTM1 and GSTT1 polymorphisms were determined by PCR-based analysis in 75 lung cancer patients and 55 controls. The unconditional logistic regression analysis was used to calculate ORs and 95% CI. The frequencies of GSTM1 and GSTT1 null genotypes were 37.3 and 22.7% in lung cancer patients and 27.3 and 16.4% in controls, respectively. When analyzed by histology the GSTM1 null genotype was more prevalent in squamous-cell carcinoma and adenocarcinoma patients. Whereas, GSTT1 null genotype frequency was lower in small-cell lung cancer patients than controls. But these differences were not statistically significant. According to smoking status, null genotype for both gene are associated with an increase in risk for lung cancer. Our results suggest that GSTM1 and GSTT1 polymorphisms may play a role in the development of lung cancer for some histological subtypes and modifies the risk of smoking-related lung cancer.
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PMID:Investigation of glutathione S-transferase M1 and T1 deletions in lung cancer. 1966 96


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