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)

The synthesis and characterization of the organotin compounds [(n-C(4)H(9))(2)Sn(cys)] (1), [(C(6)H(5))(2)Sn(cys)] (2), [(C(6)H(5))(3)Sn(Hcys).(H(2)o)] (3), {[(CH(3))(2)Sn(Kcys)(2)].2(H(2)0)} (4), {[(n-C(4)H(9))(2)Sn(Kcys)(2)].2(H(2)0)} (5) and {[(C(6)H(5))(2)Sn(Kcys)(2)].2(H(2)0)} (6) (where H(2)cys = L-cysteine) are reported. The compounds have been characterized by elemental analysis and (1)H-NMR, Uv-Vis, FT-IR and MOssbauer spectroscopic techniques. Attempted recrystallization of (2) in DMSO/methanol 2:1 solution yielded after several days unexpectedly the dimeric compound bis(tri-phenyltin)sulphide {[(C(6)H(5))(3)Sn](2)S} (7) which has been characterized by x-ray analysis. The structure of the parent complex (2) as well as the mechanism of the decomposition of cysteine are being further investigated. The in vitro anticancer activity of complexes (I)- (6), against human leukemia (HL60), human liver (Bel7402), human stomach (BGC823) and human cervix epithelial human carcinoma (Hela), nasopharyngeal carcinoma (KB) and lung cancer (PG) tumor cells, were evaluated.
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PMID:Organotin(IV) derivatives of L-cysteine and their in vitro anti-tumor properties. 1836 68

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

Here we report that human nonsmall cell lung carcinomas overexpress macrophage migration inhibitory factor (MIF) and thioredoxin (Trx), 2 oxidoreductases with cytokine function, and contain more abundant nonprotein thiols (glutathione and cysteine) than nonneoplastic lung tissues. Cell clones derived from the same lung carcinoma cell lines but expressing different levels of Trx and/or MIF displayed growth rates in vitro and in vivo correlating with Trx but not with MIF. Interestingly, the different clones generate extracellularly reduced nonprotein thiols, in amounts related to the Trx content and inhibited by inhibitors of Trx function. Each clone also showed distinct responses to the prooxidant compound arsenic trioxide. Cells with a strongly antioxidant and aggressive phenotype were more susceptible to the cytotoxic effect of the drug than cells expressing little Trx. The latter counteracted the oxidative stress by increasing Trx expression and thiol release. Together these results indicate that different human lung cancer cell lines have distinct redox properties defined by the levels of Trx and nonprotein thiols, the higher antioxidant phenotype correlating with the higher aggressiveness. Moreover, the redox phenotype dictates their response to prooxidant drugs and must be taken into account when therapeutic interventions with redox active substances are considered.
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PMID:The redox state of the lung cancer microenvironment depends on the levels of thioredoxin expressed by tumor cells and affects tumor progression and response to prooxidants. 1866 23

Human mutant-type (mt) p53 cDNA was synthesized and cloned from human lung cancer cell line GL containing mt-p53 gene by using polymerase chain reaction (PCR). It was confirmed that the mt-p53 cDNA contained the complete coding sequence of p53 gene but mutated at codon 245 (G-->T) and resulted in glycine to cysteine by sequencing analysis. The retroviral vector pD53M of the mt-p53 was constructed and introduced into the drug-sensitive human lung cancer cells GAO in which p53 gene did not mutate. The transfected GAO cells strongly expressed mutant-type p53 protein by immunohistochemistry, showing that pD53M vector could steadily express in GAO cells. The drug resistance to several anticancer agents of GAO cells infected by pD53M increased in varying degrees, with the highest increase of 4-fold,in vitro andin vivo. By quantitative PCR and flow cytometry (FCM) analyses, the expression of MDR1 gene and the activity of P-glycoprotein (Pgp) did not increase, the expression of MRP gene and the activity of multidrug resistance-related protein (Mrp) increased slightly. These results indicated that the drug resistance associated with mt-p53 gene might be somewhat correlated with MRP/Mrp but not with MDR1/Pgp. It was possible to modify the tumor drug resistance by changing status of p53 gene.
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PMID:Increasing drug resistance in human lung cancer cells by mutant-type p53 gene mediated by retrovirus. 1872 4

In this study, we carried out a radioimmunoconjugation using (177)Lu with anti-CD105 (endoglin) monoclonal antibody for an angiogenesis targeting. CD105 has been shown to be a more useful marker to identify proliferating endothelium involved in tumor angiogenesis than panendothelial markers. We optimized the labeling of the anti-CD105 monoclonal antibody with (177)Lu by using cysteine derivative isothiocyanatobenzyl-DTPA (DTPA-NCS) as BFCA. Under the optimal conditions, labeling yield was greater than 99%. Immunoactivity of the radioimmunoconjugate was investigated using combinations of radioanalytical and bioanalytical techniques (ITLC-SG, Cyclone phosphorimager, SDS-PAGE and ELISA). For the biological evaluations we carried out a cell binding assay and a biodistribution study using mice bearing Calu6 lung cancer cell xenografts. The tumor-to-blood ratio was 11.16:1 24h post-injection. In conclusion, the anti-CD105 monoclonal antibody for an angiogenesis targeting was effectively radioconjugated with (177)Lu. And the biodistribution study showed a high specificity for accumulating in tumor tissues. This radioimmunoconjugate is applicable to detect angiogenesis sites in various diseases and to treat tumors.
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PMID:Radiolabeling of monoclonal anti-CD105 with (177)Lu for potential use in radioimmunotherapy. 1932 61

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

Lung cancer is the most important cause of death among neoplastic diseases worldwide, and cigarette smoke (CS) is the major risk factor for cancer. Complementarily to avoidance of exposure to CS, chemoprevention will lower the risk of cancer in passive smokers, ex-smokers, and addicted current smokers who fail to quit smoking. Unfortunately, chemoprevention clinical trials have produced disappointing results to date and, until recently, a suitable animal model evaluating CS carcinogenicity was not available. We previously demonstrated that mainstream CS induces a potent carcinogenic response when exposure of mice starts at birth. In the present study, neonatal mice (strain H) were exposed to CS for 120 consecutive days, starting at birth. The chemopreventive agents budesonide (2.4 mg/kg diet), phenethyl isothiocyanate (PEITC, 1,000 mg/kg diet), and N-acetyl-L-cysteine (NAC, 1,000 mg/kg body weight) were administered orally according to various protocols. The experiment was stopped after 210 days. Exposure to CS resulted in a high incidence and multiplicity of benign lung tumors and in significant increases of malignant lung tumors and other histopathological alterations. All three chemopreventive agents, administered to current smokers after weaning, were quite effective in protecting both male and female mice from CS pulmonary carcinogenicity. When given to ex-smokers after withdrawal of exposure to CS, the protective capacity of budesonide was unchanged, while PEITC lost part of its cancer chemopreventive activity. In conclusion, the proposed experimental model provides convincing evidence that it is possible to prevent CS-induced lung cancer by means of dietary and pharmacological agents.
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PMID:Prevention of cigarette smoke-induced lung tumors in mice by budesonide, phenethyl isothiocyanate, and N-acetylcysteine. 1981 28

The goal of this study is to design new (99m)Tc-radiolabelled shortened CCK derivatives that might be suitable for the molecular imaging of cholecystokinin-2 receptors (CCK2-R), these receptors being over-expressed in a number of neuroendocrine tumors such as medullary thyroid cancer and small-cell lung cancer. For this purpose, we designed several modified CCK4 analogs bearing an ON(2)S tetradentate chelating agent at the N-terminus, the CCK4 sequence representing the minimal peptide sequence that presents nanomolar affinity and activity towards the CCK2-R. Four peptide conjugates of general formula (Trt)SN(2)OPh-(X)(n)-CCK4 (X=beta-alanine or 6-aminohexanoic acid spacers; n=0, 2, 4) and their oxorhenium peptide conjugates have been synthesized and characterized. In vitro evaluation of these compounds showed a close relationship between the nature and the length of the spacer and the corresponding binding affinity values. The most promising oxorhenium complex 5-Re exhibited potent CCK2-receptor agonist properties in promoting the production of inositol phosphate in COS-7 cells (EC(50)=5.17nM). Preliminary (99m)Tc-radiolabelling studies with peptide conjugates 3 or 5 led exclusively to the corresponding (99m)TcO-complexes 3-Tc and 5-Tc, which exhibited high resistance towards an excess of cysteine and satisfactory stabilities in human serum. To conclude, the promising in vitro characteristics of compounds 5-Re, 5-Tc illustrate the feasibility to develop stable radiolabelled shortened CCK4 derivatives with a nanomolar CCK2-R affinity.
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PMID:Synthesis, characterization and in vitro evaluation of new oxorhenium- and oxotechnetium-CCK4 derivatives as molecular imaging agents for CCK2-receptor targeting. 1985 77

Irreversible EGFR inhibitors can circumvent acquired resistance to first-generation reversible, ATP-competitive inhibitors in the treatment of non-small-cell lung cancer. They contain both a driver group, which assures target recognition, and a warhead, generally an acrylamide or propargylamide fragment that binds covalently to Cys797 within the kinase domain of EGFR. We performed a systematic exploration of the role for the warhead group, introducing different cysteine-trapping fragments at position 6 of a traditional 4-anilinoquinazoline scaffold. We found that different reactive groups, including epoxyamides (compounds 3-6) and phenoxyacetamides (compounds 7-9), were able to irreversibly inhibit EGFR. In particular, at significant lower concentrations than gefitinib (1), (2R,3R)-N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(piperidin-1-ylmethyl)oxirane-2-carboxamide (6) inhibited EGFR autophosphorylation and downstream signaling pathways, suppressed proliferation, and induced apoptosis in gefitinib-resistant NSCLC H1975 cells, harboring the T790M mutation in EGFR.
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PMID:Novel irreversible epidermal growth factor receptor inhibitors by chemical modulation of the cysteine-trap portion. 2015 70


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