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)

Hydrogen peroxide (H2O2) and other oxygen metabolites have been implicated in the pathogenesis of cell and tissue injury. The nature of the injury occurring in cells exposed to oxygen metabolites is unknown. A549 cells, derived from human lung carcinoma, were exposed to glucose-glucose oxidase or hydrogen peroxide in vitro. The distribution of actin and cytokeratin filaments, as well as 51chromium (51Cr) release and trypan blue dye exclusion were assessed. Both glucose-glucose oxidase and H2O2 resulted in changes which were time- and dose-dependent. Alterations in the cytoskeleton were detected by immunofluorescence microscopy at two hours, at which time the cells excluded trypan blue dye, while 51Cr release and trypan blue uptake first occurred at 8 h and required a five-fold greater concentration of glucose oxidase. The addition of catalase to glucose-glucose oxidase or H2O2, or inactivation of glucose oxidase by boiling, abrogated the injury. Therefore, one of the early targets of H2O2-induced cell injury may be the cytoskeleton.
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PMID:Cytoskeletal changes as an early event in hydrogen peroxide-induced cell injury: a study in A549 cells. 241 61

Misonidazole is a metabolically active drug. Its addition to cells causes an immediate alteration in cellular electron transfer pathways. Under aerobic conditions the metabolic alterations can result in futile cycling with electron transfer to oxygen and production of peroxide. Thiol levels are extremely important in protecting the cell against the peroxide formation and potentially hazardous conditions for hydroxyl radical production. Nevertheless such electron shunting out of cellular metabolism will result in alterations in pentose cycle, glycolysis and cellular capacity to reduce metabolites to essential intermediates needed in DNA metabolism (i.e. deoxyribonucleotides). Glutathione must be depleted to very low levels before toxic effects of misonidazole and other nitro compounds are manifested in cell death via peroxidative damage. Under hypoxic conditions misonidazole also diverts the pentose cycle via its own reduction; however, unlike the aerobic conditions, there are a number of reductive intermediates produced that react with non-protein thiols such as GSH as well as protein thiols. The reaction with protein thiols results in the inhibition of glycolysis and other as yet undetermined enzyme systems. The consequences of the hypoxic pretreatment of cells with nitro compounds are increased vulnerability to radiation and chemotherapeutic drugs such as L-PAM, cis-platinum and bleomycin. The role that altered enzyme activity has in the cellular response to misonidazole and chemotherapeutic agents remains to be determined. It is also clear that the GSH depleted state not only makes cells more vulnerable to oxidative stress but also to hypoxic intermediates produced by the reduction of misonidazole beyond the one electron stage. The relevancy of the present work to the proposed use of thiol depletion in vivo to enhance the radiation or chemotherapeutic response of tumor tissue lies with the following considerations. Apparently, spontaneous peroxidative damage to normal tissue such as liver can occur with GSH depletion to 10-20% of control and with other normal tissue when GSH reaches 50% of control. This situation can obviously become more critical if peroxide producing drugs are administered. The only advantage to such combined drug treatments would lie in the possibility that tumors vary in their catalase and peroxidase activity and consequently may be more vulnerable to oxidative stress (cf. review by Meister. Our tumor model, the A549 human lung carcinoma cell in vitro, appears to be an exception because it has catalase, peroxidase and a high content of GSH.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biochemistry of reduction of nitro heterocycles. 293 68

Chronic aerobic exposure of A549 human lung carcinoma cell cultures to 0.1 mM L-buthionine-S,R-sulfoximine and 1 mM misonidazole, or 1 mM SR-2508 results in inhibition of cell growth and decreased clonogenic survival. These patterns are not apparent with the individual drug treatments. Both parameters demonstrate maximum toxicity after 72 hr in culture, which parallels the time required to deplete A549 cells of glutathione with 0.1 mM L-BSO under these growth conditions. Toxicity appears to be related to hydrogen peroxide-produced during 1 electron reduction of the nitro compounds in the presence of oxygen. A549 cells have a lowered capacity to reduce peroxide due to the effect of thiol depletion on the enzymes GSH-peroxidase and GSH-S-transferase, which require the tripeptide as a substrate. The addition of catalase, another important enzyme involved in peroxide reduction, partially reverses the observed toxicity. 4-Hydroxypyrazole, which inhibits endogenous catalase activity, causes an increase in the observed cytotoxicity. Similar effects of L-BSO and 4-hydroxypyrazole are seen for toxicity due to hydrogen peroxide being added directly to cell cultures.
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PMID:Enhancement in the aerobic toxicity of misonidazole and SR-2508 by buthionine sulfoximine and 4-hydroxypyrazole: the role of hydrogen peroxide. 294 13

In two Adriamycin (Adr) resistant sublines (GLC4-Adr1 and GLC4-Adr2) of a human small cell lung carcinoma cell line, GLC4, cross-resistance for radiation was found. GLC4-Adr1 has an acquired Adr resistance factor of 44 after culturing without Adr for 20 days and GLC4-Adr2, the same subline cultured without Adr for 3 months, has a decreased but stable resistance factor of 8. One of the assumed mechanisms of Adr is that the effect is mediated through the formation of free radicals. Therefore free radical scavenging might play a role in these Adr resistant cell lines. Adr, H2O2, and X-ray induced cytotoxicity were evaluated. Glutathione (GSH) levels and activities of associated enzymes were determined as well as Adr, H2O2, and X-ray induced DNA breaks and repair. GSH level was decreased in GLC4-Adr1, but restored to the normal level in GLC4-Adr2. Superoxide dismutase, catalase, glutathione-peroxidase, and glutathione S-transferase were not elevated in the resistant sublines. Adr induced a decreased amount of DNA breaks in GLC4-Adr1 compared to GLC4. For X-ray and H2O2 a comparable amount of DNA damage was found. GLC4-Adr1 was able to repair DNA breaks induced by Adr, X-ray, and H2O2 better than GLC4. In conclusion, no increased enzyme capacity for detoxification of free radicals could be detected in the cytosol of the resistant cells. The resistance against free radicals in the GLC4-Adr1 line may at least in part be a result of increased DNA repair.
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PMID:Role of free radicals in an adriamycin-resistant human small cell lung cancer cell line. 304 Feb 27

The capacity of alveolar macrophages from mice injected with a metastatic Lewis lung carcinoma variant, LLC-C3, to regulate T-cell Con A blastogenesis and NK cytotoxicity was studied. During the first 5 days after subcutaneous tumor injection, alveolar macrophages were stimulatory to Con A blastogenesis of normal spleen cells. After 5 days, the alveolar macrophages shifted to become suppressive. The suppressive activity was extensive by day 11, when the primary and metastatic tumor foci were first detectable. The tumor-bearer alveolar macrophages also suppressed NK cytotoxicity. Alveolar macrophage suppressive activity was sensitive to indomethacin, suggesting a prostaglandin-dependent suppressor mechanism. Suppression was not mediated by the production of hydrogen peroxide or superoxide, as it was insensitive to catalase or superoxide dismutase. When normal alveolar macrophages were cultured with LLC-C3 supernatants for over 12 hours, suppressive activity was induced. The results of these studies show that alveolar macrophages of tumor bearers become suppressive with progressive tumor growth and might, thus, facilitate the development of pulmonary metastases.
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PMID:Suppressor alveolar macrophages in mice bearing metastatic Lewis lung carcinoma tumors. 350 Feb 55

Human monomorphonuclear leukocytes (MMNs) stimulated with 12-O-tetradecanoylphorbol-13-acetate (TPA) were found to be toxic towards human A549 lung carcinoma cells which have been desensitized against the direct growth-inhibitory effect of TPA. This toxicity was dependent on the TPA concentration and the ratio of MMNs to A549 cells. Using a TPA concentration of 10(-7) M and an effector:target cell ratio of 30:1, experiments were performed to give clues as to the mechanisms by which TPA-stimulated MMNs cause toxicity. Levels of the endogenous thiol glutathione were reduced by 37% in MMNs exposed to TPA for 24 h, but the glutathione levels in the A549 target cells were not markedly affected by TPA-stimulated MMNs. The supernatant of incubations of MMNs with TPA contained a species which was capable of oxidizing the thiol agent 5-thio-2-nitrobenzoic acid. Within 2 h, 9 nmol of this oxidant were produced by 10(7) MMNs. The oxidant exhibited a half-life of 20 h, and its formation was abolished by adding catalase (150 units/ml), azide (1 mM), or cyanide (1 mM) to the incubations of MMNs with TPA. The addition of superoxide dismutase (100 units/ml) enhanced oxidant formation. These results indicate that its generation was dependent on the myeloperoxidase:H2O2:halide system. Large amounts of an oxidizing species with properties identical to those described here have been characterized recently in polymorphonuclear leukocytes [S. J. Weiss, M. B. Lampert, and S. T. Test. Science (Wash. DC), 222: 625-627, 1983]. The toxicity exerted by TPA-stimulated MMNs was partially inhibited by superoxide dismutase and by retinoic acid (30 microM) but not at all by catalase, azide, or cyanide. Therefore, the 5-thio-2-nitrobenzoic acid oxidant does not appear to be involved in the process which led to cytotoxicity by TPA-stimulated MMNs in A549 cells.
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PMID:Oxidative properties of 12-O-tetradecanoylphorbol-13-acetate-stimulated human blood monomorphonuclear leukocytes and their toxicity against a human lung carcinoma cell line. 397 31

This study demonstrates that viable Mycoplasma pneumoniae cells inhibit catalase activity in several types of intact human cells as well as in solution. Human erythrocyte catalase was inhibited up to 72%, and the inhibition of catalase in human cultured skin fibroblasts, lung carcinoma epithelial cells, and ciliated epithelial cells from human nasal polyps ranged between 75 and 80%. UV light-killed mycoplasmas failed to inhibit catalase activity both in intact cells and in vitro. After M. pneumoniae infection of human cultured skin fibroblasts, the level of malonyldialdehyde, an indicator for membrane lipid peroxidation, was 3.5 times higher than in control fibroblasts. Virulent M. pneumoniae completely inhibited catalase activity in solution, whereas the nonvirulent strains had a lesser ability to inhibit catalase activity. These findings suggest that as a result of host cell catalase inhibition by M. pneumoniae, the toxicity of the hydrogen peroxide generated by the microorganism and the affected cell is enhanced, thereby inducing host cell damage.
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PMID:Inhibition of host cell catalase by Mycoplasma pneumoniae: a possible mechanism for cell injury. 640 99

Misonidazole, SR-2508, nitrofurazone and other nitroheterocycles stimulated release of 14CO2 from [1-14C]glucose but not from [6-14C]glucose when incubated with mouse Ehrlich ascites cells or human A549 lung carcinoma cells in vitro. This demonstrated that the nitro compounds activated the hexose monophosphate shunt and is evidence that an important pathway of nitro reduction in these cell lines is electron transfer from NADPH-dependent cytochrome c reductase to the nitro group. Shunt activity was stimulated under both aerobic and anaerobic conditions. For catalase-free Ehrlich cells, aerobic effects were greater than anaerobic, indicating that NADPH was used for reduction of H2O2, via GSH peroxidase and reductase, as well as for one-electron nitro reduction, under aerobic conditions. Several of the compounds tested stimulated 14CO2 release from [2-14C]glucose as well as from [1-14C]-glucose. This shows that the cellular requirement for NADPH, in the presence of nitro drug, was great enough to cause recycling of pentose phosphates. Recycling could decrease the availability of ribose-5-P needed for nucleic acid synthesis, which could partly explain the inhibition of DNA synthesis observed upon prolonged aerobic incubation of cells with nitro compounds. Comparison of the rate of disappearance of nitrofurazone from anaerobic A549 cell suspensions with the rate of 14CO2 release suggests that the drug reduction in this cell line was catalyzed almost entirely by NADPH-requiring enzymes.
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PMID:Nitroheterocycle metabolism in mammalian cells. Stimulation of the hexose monophosphate shunt. 642 13

Cigarette smoke polyphenolic agents (catechol and hydroquinone) that generate oxidants have been shown to be tumor promoters. Furthermore, oxidants can influence protein kinase C (PKC)-mediated signal transduction. Since terpenoid tumor promoters, phorbol esters, increase invasion and metastasis by activating PKC, we have determined whether polyphenolic agents present in the cigarette smoke condensate (CSC) could also influence these events. Hydroquinone (50 microM), catechol (500 microM), or CSC (50 micrograms/ml) induced an initial cytosol-to-membrane translocation of PKC in LL/2 lung carcinoma cells, followed by a later down-regulation of the enzyme. LL/2 cells treated with these CSC-related agents for a limited time (45 min) and exhibiting high membrane-associated PKC activity, when injected into mice through the tail vein, produced an increase in metastatic nodules in the lungs after 20 days. However, cells treated with CSC-related agents for a prolonged period did not exhibit an increase in metastasis. Agents that decrease the rate of production of reactive oxygen species, such as catalase either alone or in combination with superoxide dismutase, and a cell-permeable iron-chelator, o-phenanthroline, inhibited CSC-mediated membrane association of PKC and metastasis. Prior treatment of CSC with tyrosinase to modify polyphenols resulted in a partial loss of CSC stimulation of metastasis. Furthermore, a cell-permeable Ca2+ chelator and diverse PKC inhibitors, such as calphostin C, hypericin, chelerythrine, and bisindolylmaleimide, inhibited CSC-enhanced metastasis. CSC increased in vitro tumor cell adhesion to endothelial monolayers and to reconstituted basement membrane (Matrigel) and also enhanced the invasion through Matrigel coated on the polycarbonate filters in Transwells. All these CSC effects were found to be temporary and were blocked by the above mentioned antioxidant systems and PKC inhibitors. Thus, these results suggest that the oxidants generated by autooxidation of polyphenolic agents present in tobacco smoke increase tumor cell invasion and metastasis, at least in part by activation of Ca2+/PKC signal transduction. Conceivably, cigarette smoke constituents not only promote tumorigenesis but also may increase the spread of cancer in the body.
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PMID:Tobacco smoke tumor promoters, catechol and hydroquinone, induce oxidative regulation of protein kinase C and influence invasion and metastasis of lung carcinoma cells. 799 11

The expression of intrinsic resistance to cisplatin in two lung cancer cell lines, one derived from a small cell carcinoma (SW1271) and the other from an adenocarcinoma (A549), relative to a drug-sensitive small cell line SW900, was characterized by: (i) expression of cross-resistance to mitomycin C and cadmium chloride, but increased sensitivity to adriamycin and etoposide; (ii) significantly decreased cisplatin uptake; (iii) elevated levels of glutathione which could be reduced by buthionine L-sulfoximine resulting in significant sensitization of the cells to cisplatin; (iv) a lack of consistent modification of metallothionein content and expression of levels of glutathione S-transferase, glutathione reductase and glutathione peroxidase or of activities of DT-diaphorase or catalase; (v) significantly reduced total DNA-platination levels immediately following a 1 h cisplatin treatment with 10 micrograms/ml (33.3 microM); (vi) increased removal of Pt-GG and Pt-AG adducts by the A549 cells, consistent with increased repair capacity, but a lack of removal of these major adducts by the SW1271 cells indicative of tolerance of this drug-induced DNA damage. These data therefore provide evidence of differential formation, repair and tolerance of DNA damage following exposure of three human lung carcinoma cell lines to cisplatin.
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PMID:Evidence of differential cisplatin-DNA adduct formation, removal and tolerance of DNA damage in three human lung carcinoma cell lines. 840 Mar 52


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