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)

This study was designed to assess the effect of differential leukocyte depletion during chemotherapy by monitoring the levels of exhaled hydrogen peroxide H2O2 and nitric oxide (F(eNO)) present. In 39 patients with lung cancer (chronic obstructive pulmonary disorder up to stage II, median forced expiratory volume in one second 78% predicted), measurements were performed before a cycle of therapy (day 1), at least once during the cycle (day 8: n = 34; day 15: n = 19), and afterwards (days 21-29). There were significant changes in the level of H2O2, F(eNO) and peripheral blood cell differentials over the visits. The level of H2O2 was decreased only on day 15, with a median (difference between the upper and lower quartiles) fall of 31 (57)%, while F(eNO) was reduced only on day 8, by 22 (40)%. Neutrophil numbers were unchanged on day 8 and decreased by 59 (48)% on day 15, while monocyte numbers were decreased on day 8 by 87 (39)%. On days 21-29, values had returned to baseline. Taken together with previous findings, the parallel course of levels of exhaled hydrogen peroxide and neutrophil counts suggests that a major part of exhaled hydrogen peroxide is due to neutrophils via the conducting airways. In contrast, the production of exhaled nitric oxide seems to be primarily associated with monocytes.
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PMID:Time course of exhaled hydrogen peroxide and nitric oxide during chemotherapy. 1670 98

Cisplatin is a potent cytotoxic agent commonly used for the treatment of solid tumors. However, tumor cell-acquired resistance to cisplatin-induced apoptosis is a major limitation for efficient therapy, as frequently observed in human lung cancer. Nitric oxide (NO) is a key regulator of apoptosis, but its role in cisplatin-induced cell death and the underlying mechanism are largely unknown. Previous studies indicate increased NO synthase activity and elevated NO production in lung carcinomas, which correlate with the incidence of chemotherapeutic resistance. Here, we show that NO impairs the apoptotic function of cells and increases their resistance to cisplatin-induced cell death in human lung carcinoma H-460 cells. The NO donors sodium nitroprusside and dipropylenetriamine NONOate were able to inhibit cisplatin-induced cell death, whereas the NO inhibitors aminoguanidine and 2-(4-carboxyphenyl)-4,4,5,5-tetra-methylimidazoline-1-oxyl-3-oxide had opposite effect. Cisplatin resistance in H-460 cells is mediated by Bcl-2, and NO up-regulates its expression by preventing the degradation of Bcl-2 via ubiquitin-proteasome pathway. Cisplatin-induced generation of reactive oxygen species causes dephosphorylation and degradation of Bcl-2. In contrast, generation of NO has no effect on Bcl-2 phosphorylation but induces S-nitrosylation of the protein, which inhibits its ubiquitination and subsequent proteasomal degradation. These findings indicate a novel pathway for NO regulation of Bcl-2, which provides a key mechanism for cisplatin resistance and its potential modulation for improved cancer chemotherapy.
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PMID:Nitric oxide regulates cell sensitivity to cisplatin-induced apoptosis through S-nitrosylation and inhibition of Bcl-2 ubiquitination. 1677 13

Heme oxygenase (HO)-1 is a key player reducing cytotoxicity and enhancing protumoral effects of nitric oxide (NO). We examined zinc protoporphyrin (ZnPP) IX, an HO-1 inhibitor, to affect tumor growth of LL/2 mouse lung cancer cells. ZnPPIX reduced HO-1 expression and HO activity in LL/2 cells, whereas cobalt PPIX (CoPPIX), an HO-1 activator, increased both. LL/2 cells treated with sodium nitropurusside, an NO donor, showed growth inhibition dose-dependently, which was enhanced by ZnPPIX cotreatment, but was reduced by CoPPIX. In mice tumors, ZnPPIX decreased HO-1 expression. LL/2-tumors were found in 88% (7/8) vehicle-treated mice, whereas tumors were found in 38% (3/8) and 25% (2/8) mice treated with 5 and 20 microg/mouse ZnPPIX, respectively (p = 0.0302). Tumor growth was inhibited dose-dependently by ZnPPIX. Vascular endothealial growth factor concentration in tumors was reduced by ZnPPIX (p = 0.0341). Microvessel density (MVD) in ZnPPIX-treated tumors was lower than that in vehicle-treated tumors (p = 0.0362). Apoptotic cell count in ZnPPIX-treated tumors was higher than that in vehicle-treated tumors (p = 0.0003). In contrast, CoPPIX treatment increased HO-1 expression, enhanced tumorigenicity and MVD and reduced apoptosis. From these findings, inhibition of HO-1 by ZnPPIX provides relevant antitumoral effects.
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PMID:Inhibition of heme oxygenase-1 by zinc protoporphyrin IX reduces tumor growth of LL/2 lung cancer in C57BL mice. 1706 48

Nitric oxide has been extensively studied as a noninvasive marker of airway inflammation. Assuming that bronchoscopy can produce not only systemic but also local inflammatory response, we hypothesized that bronchofiberoscopy can be responsible for an increase in nitric oxide synthesis with resulting increase in fractional concentration of exhaled nitric oxide (FE(NO)). Fifty five subjects (F/M-23/32; mean age 53.9 +/-17.3 yr) undergoing diagnostic bronchoscopy participated in the study. The indications for bronchoscopy were as follows: interstitial lung diseases (n=13; 23.6%), lung cancer (n=11; 20.0%), hemoptysis (n=10; 18.2%), differential diagnosis of asthma/dyspnea (n=9; 16.4%), pulmonary infections (n=7; 12.7%), and others (n=5; 9.1%). During bronchoscopy bronchial washing (n=18), bronchoalveolar lavage (BAL) (n=26), and bronchial biopsies (n=24) were performed. FE(NO) was analyzed on-line with chemiluminescence analyzer (NIOX, Aerocrine, Sweden) according to the ATS guidelines, before and at 1, 2, 3 and 24 h after bronchoscopy. The mean FE(NO) before bronchoscopy was 21.0 +/-3.31(SE) ppb, it decreased to 14.8 +/-2.10 ppb 1 h after bronchoscopy, reached a nadir at 2 h (14.4 +/-2.28 ppb; P<0.05), and was not different from baseline 24 h after bronchoscopy (22.8 +/-2.90 ppb). There were no differences in the FE(NO) profile in BAL patients compared with those in whom only the bronchial washing was performed. We conclude that bronchoscopy leads to a decrease in FE(NO). The underlying mechanisms are at present unclear.
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PMID:The effect of fiberoptic bronchoscopy on exhaled nitric oxide. 1707 45

Nine derivatives of three natural diarylheptanoids, curcumin, demethoxycurcumin and bisdemethoxycurcumin, were prepared. Their antioxidant, free radical scavenging, nitric oxide (NO) inhibitory and cytotoxic activities were evaluated and compared with those of the respective natural compounds. Curcumin (1), demethoxycurcumin (2), demethyldemethoxy-curcumin (C3), diacetyldemethoxycurcumin (AC2) and triacetyldemethylcurcumin (AC5) exhibited higher antioxidant activity than quercetin while products from demethylation of 1 and 2 exhibited higher free radical scavenging activity. Compounds AC2 and AC5 were found to be most active in inhibiting breast cancer cells (MCF-7) proliferation with IC50 values of 6.7 and 3.6 microM, respectively. The activity of AC2 is almost doubled and of AC5 almost tripled as compared to curcumin. Their selectivity towards different cell lines is also more noticeable. Compounds AC2 and AC5 also showed increased activity against a human prostate cancer cell line (DU-145) and non-small lung cancer cell line (NCI-H460) with IC50 values of 20.4, 16.3 and 18.3, 10.7 microM, respectively.
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PMID:Biological evaluation of curcumin and related diarylheptanoids. 1713 4

Diesel exhaust particles are major constituents of ambient air pollution, and are associated with respiratory and cardiovascular diseases and lung cancer. The organic part of the particles is heterogenic and complex, and seems to be responsible for many of the adverse effects. Increased formation of ROS is often connected to the adverse effects. We have therefore investigated the effect of an organic extract of diesel exhaust particles on the reactive oxygen species (ROS) status in human neutrophil granulocytes and rat alveolar macrophages in vitro. ROS formation were studied by three different assays namely the use of DCFH-DA, lucigenin and luminol. The organic extract increased ROS assayed with DCFH-DA, but it decreased the amount of ROS in cells stimulated by PMA in all three assays. The identities of the ROS affected were further studied in cell free systems. The cell free studies confirmed that the extract had scavenging effects against superoxide, hypochlorite and to a smaller extent against peroxynitrite, but not against the hydroxyl radical and nitric oxide. ROS take part in the intracellular signalling pathways as well as in the defence against invading microorganisms, and the possible effects of interference of the redox status in the cells are discussed.
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PMID:ROS scavenging effects of organic extract of diesel exhaust particles on human neutrophil granulocytes and rat alveolar macrophages. 1717 87

Inducible nitric oxide synthase (iNOS) is one of three enzymes generating nitric oxide (NO) from the amino acid L-arginine. iNOS-derived NO plays an important role in several physiological and pathophysiological conditions. NO is a free radical which produces many reactive intermediates that account for its bioactivity. In the human lung, the alveolar macrophage is an important producer of cytokines and this production may be modified by NO. Moreover, high concentrations of NO have been shown to increase nuclear factor kappaB (NF-kB) activation. Recent investigations of NO expression in tumor tissue indicated that, at least for certain tumors, NO may mediate one or more roles during the growth of human cancer. We have studied iNOS in two tissue groups: normal human lung tissue and human lung cancer tissue. We localized iNOS in these tissues by immunohistochemistry and tested the mRNA expression by RT-PCR, the protein level by Western blot, and the protein activity by radiometric analysis. The results demonstrate different expression, localization and activity of iNOS in normal versus tumor tissue. This is suggestive of a role for NO production from iNOS in human lung cancer because high concentrations of this short molecule may transform to highly reactive compounds such as peroxynitrite (ONOO-); moreover, through the upregulator NF-kB, they can induce a chronic inflammatory state representing an elevated risk for cell transformation to cancer.
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PMID:Localization and activity of iNOS in normal human lung tissue and lung cancer tissue. 2820 21

Epidermal growth factor receptor (EGFR) is activated by ionizing radiation (IR), but the molecular mechanism for this effect is unknown. We have found that intracellular generation of nitric oxide (NO) by NO synthase (NOS) is required for the rapid activation of EGFR phosphorylation by IR. Treatment of A549 lung cancer cells with IR increased NOS activity within minutes, accompanied by an increase of NO. 2-Phenyl-4,4,5,5,-tetramethylimidazolline-1-oxyl-3-oxide, an NO scavenger, and NG-monomethyl-l-arginine, an NOS inhibitor, abolished the increase in intracellular NO and activation of EGFR by IR. In addition, an NO donor alone induced EGFR phosphorylation. Transient transfection with small interfering RNA for endothelial NOS reduced IR-induced NO production and suppressed IR-induced EGFR activation. Overexpression of endothelial NOS increased IR-induced NO generation and EGFR activation. These results indicate a novel molecular mechanism for EGFR activation by IR-induced NO production via NOS.
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PMID:Activation of epidermal growth factor receptor and its downstream signaling pathway by nitric oxide in response to ionizing radiation. 1856 3

Lung cancer is a leading cause of cancer death, with the prognosis adversely affected by late diagnosis. Early diagnosis of lung cancer is desirable, but current evidence does not support the application of screening with techniques such as chest radiography, sputum cytology or computed tomography. Breath analysis, which includes gaseous phase analysis that measures volatile organic compounds using electronic noses, exhaled nitric oxide, and exhaled breath condensate (EBC), has been proposed as a non-invasive and simple technique to investigate neoplastic processes in the airways. EBC can be easily collected by breathing into a cooling system that condenses the water vapour in the breath. EBC has already been demonstrated to be useful in investigating inflammatory and oxidative stress changes in various respiratory conditions as it contains measurable mediators of airway inflammation and oxidative stress markers. Furthermore, EBC has also been shown to be a useful method to monitor severity of diseases such as asthma and to act as a surrogate measure of compliance to medical therapy. Presently, there still remains a relative paucity of lung cancer research involving EBC. However, since EBC is a simple, non-invasive technique that can be easily performed, even in ill patients, it has the potential to be validated for use in screening for the early diagnosis of lung cancer.
Lung Cancer 2009 Feb
PMID:Exhaled breath analysis: novel approach for early detection of lung cancer. 1859 52

Nitric oxide ((.)NO) induces apoptosis at high concentrations by S-nitrosating proteins such as glyceraldehyde-3-phosphate dehydrogenase. This literature analysis revealed that failure to sustain high (.)NO concentrations is common to all cancers. In cervical, gastric, colorectal, breast, and lung cancer, the cause of this failure is the inadequate expression of inducible nitric oxide synthase (iNOS), resulting from the inhibition of iNOS expression by TGF-beta1 at the mRNA level. In bladder, renal, and prostate cancer, the reason for the insufficient (.)NO levels is the depletion of arginine, resulting from arginase overexpression. Arginase competes with iNOS for arginine, catalyzing its hydrolysis to ornithine and urea. In gliomas and ovarian sarcomas, low (.)NO levels are caused by inhibition of iNOS by N-chlorotaurine, produced by infiltrating neutrophils. Stimulated neutrophils express myeloperoxidase, catalyzing H2O2 oxidation of Cl- to HOCl, which N-chlorinates taurine at its concentration of 19 mM in neutrophils. In squamous cell carcinomas of the skin, ovarian cancers, lymphomas, Hodgkin's disease, and breast cancers, low (.)NO concentrations arise from the inhibition of iNOS by N-bromotaurine, produced by eosinophil-peroxidase-expressing infiltrating eosinophils. Eosinophil peroxidase catalyzes the H2O2 oxidation of Br- to HOBr, which N-brominates taurine to N-bromotaurine at its concentration of 15 mM in eosinophils. In microvascularized tumors, the (.)NO concentration is further depleted; (.)NO is rapidly consumed by red blood cells (RBCs) through S-nitrosation of RBC glutathione and hemoglobin, and by oxidation to nitrate by RBC oxyhemoglobin. Angiogenesis-inhibiting antibodies are currently used to treat cancers; their mode of action is not, as previously thought, reduction of the tumor O2 or nutrient supply. They actually decrease the loss of (.)NO to RBCs.
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PMID:Apoptosis-inducing high (.)NO concentrations are not sustained either in nascent or in developed cancers. 1875 45


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