Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arsenic is a naturally occurring element that is present in food, soil, and water. Inorganic arsenic can accumulate in human skin and is associated with increased risk of skin cancer. Oxidative stress due to arsenic exposure is proposed as one potential mode of carcinogenic action. The purpose of this study is to investigate the specific reactive oxygen and nitrogen species that are responsible for the arsenic-induced oxidative damage to DNA and protein. Our results demonstrated that exposure of human keratinocytes to trivalent arsenite caused the generation of 8-hydroxyl-2'-deoxyguanine (8-OHdG) and 3-nitrotyrosine (3-NT) in a concentration- and time-dependent manner. Pentavalent arsenate had similar effects, but to a significantly less extent. The observed oxidative damage can be suppressed by pre-treating cells with specific antioxidants. Furthermore, we found that pre-treating cells with Nomega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), or with 5,10,15,20-tetrakis (N-methyl-4'-pyridyl) porphinato iron (III) chloride (FeTMPyP), a decomposition catalyst of peroxynitrite, suppressed the generation of both 8-OHdG and 3-NT, which indicated that peroxynitrite, a product of the reaction of nitric oxide and superoxide, played an important role in arsenic-induced oxidative damage to both DNA and protein. These findings highlight the involvement of peroxynitrite in the molecular mechanism underlying arsenic-induced human skin carcinogenesis.
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PMID:Inorganic arsenic compounds cause oxidative damage to DNA and protein by inducing ROS and RNS generation in human keratinocytes. 1628 19

It has been reported that increased nitric oxide synthase (NOS) expression and nitric oxide (NO) production may play an important role in cancer biology. The aim of this study was to determine the roles of NO in tumour cellular proliferation and DNA or RNA synthesis, and to investigate the therapeutic potential of NOS inhibitors in oral cancer. After exposure to different concentrations of the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), the growth of TSCCa cells, established from a patient with squamous cell carcinoma of the tongue, was evaluated using MTT and crystal violet assay. DNA or RNA synthesis, inducible/endothelial NOS (iNOS/eNOS) mRNA expression and NO production were then examined to determine the possible mechanisms of inhibitory effects of L-NAME on TSCCa cells. L-NAME had an inhibitory effect on TSCCa cell growth in both a concentration- and time-dependent manner. Acridine orange staining revealed that DNA and/or RNA synthesis of TSCCa cells was reduced after treatment with L-NAME. An in situ hybridisation (ISH) study showed clearly that L-NAME down-regulated eNOS and iNOS mRNA expression and this was followed by a decrease in NO production. It is postulated that the NOS/NO pathway may be implicated in cellular proliferation and DNA or RNA synthesis of cancer cells, apart from promoting tumour angiogenesis. Further studies have provided with new insight into the mechanisms by which NOS/NO takes part in oral carcinogenesis, and possible therapeutic interventions based on the NOS/NO pathway for tumour progression control.
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PMID:In vitro effects of nitric oxide synthase inhibitor L-NAME on oral squamous cell carcinoma: a preliminary study. 1649 78

Prevention is one of the most important and promising strategies to control cancer. Many dietary bioactive compounds, mostly phytochemicals, have been found to decrease the risk of carcinogenesis. Modulating the metabolism and disposition pathways of carcinogens represents one of the major mechanisms by which dietary compounds prevent carcinogenesis. In the present review, the specific molecular targets of dietary compounds within carcinogen metabolism, including various enzymes and transporters and their regulatory signaling pathways, are briefly reviewed. The expression of phase I enzymes, which presumably mostly activate carcinogens, is mainly regulated by xenobiotics sensing nuclear receptors such as AhR, CAR, PXR, and RXR. On the other hand, phase II enzymes catalyze the conjugations of carcinogens and generally are transcriptionally controlled by the Nrf2/ARE signaling pathways. The Nrf2/ARE signaling pathway, which regulates the expression of many detoxifying enzymes, is a major target of dietary compounds. The final excretion of carcinogens and their metabolites is mediated by phase III transporters, which share many regulatory mechanisms with phase I/II enzymes. Indeed, the expression of metabolizing enzymes and transporters is often coordinately regulated. Besides transcriptional regulation, the activities of phase I/II enzymes and phase III transporters could be directly activated or inhibited by dietary compounds. Furthermore, genetic polymorphisms have profound effects on the individual response to dietary compounds. Finally, the effects of cancer prevention and the risk of carcinogenesis are determined by the network composed of known/unknown molecular targets and signaling pathways and its interaction with various xenobiotics, including carcinogens, drugs, and diet. With the rapid advances in the post genomic sciences, it could be possible to decipher this network and better predict the clinical outcomes of cancer prevention by dietary bioactive compounds.
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PMID:Targeting carcinogen metabolism by dietary cancer preventive compounds. 1769

Both oxidative/nitrosative stress and alterations in DNA methylation are observed during carcinogenesis of different tumor types, but no clear correlation between these events has been demonstrated until now. Melanoma cell lines were previously established after submitting the nontumorigenicmelanocyte lineage, melan-a, to cycles of anchorage blockade. In this work, increased intracellular oxidative species and nitric oxide levels, as well as alterations in the DNA methylation, were observed after melan-a detachment, which were also associated with a decrease in intracellular homocysteine (Hcy), an element in the methionine (universal methyl donor) cycle. This alteration was accompanied by increase in glutathione (GSH) levels and methylated DNA content. Furthermore, a significant increase in dnmt1 and 3b expression was identified along melan-a anchorage blockade. L(G)-Nitro-L-arginine methyl esther (L-NAME), known as a nitric oxide synthase (NOS) inhibitor, and N-acetyl-L-cysteine (NAC) prevented the increase in global DNA methylation, as well as the increase in dnmt1 and 3b expression, observed during melan-a detachment. Interestingly, both L-NAME and NAC did not inhibit nitric oxide (NO) production in these cells, but abrogated superoxide anion production during anchorage blockade. In conclusion, oxidative stress observed during melanocyte anchorage blockade seems to modulate DNA methylation levels and may directly contribute to the acquisition of an anoikis-resistant phenotype through an epigenetic mechanism.
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PMID:Oxidative stress modulates DNA methylation during melanocyte anchorage blockade associated with malignant transformation. 1808 18

Risk assessment based on rodent carcinogenicity data depends on the assumption of similarity between rodents and humans. While this assumption is conceivable in the case of genotoxic initiating carcinogens, considerable species differences have been observed with nongenotoxic tumor promoters. This heterogeneous group of agents increases the probability of cancer by stimulating selection and clonal expansion of cells transformed during tumor initiation. Since tumor promoters differentially affect normal tissue and preneoplastic cell clones, their action cannot be discussed without knowledge of persistent genomic and epigenetic alterations occurring during initiation and formation of preneoplastic cells. Chemical carcinogenesis, and in particular, tumor promotion, is known to be tissue specific. We focus on hepatocarcinogenesis in humans and in animal models and emphasize two different modes of action: (1) chronic cytotoxicity leading to promotion of liver carcinogenesis in both humans and animal models; (2) sustained activation of orphan receptors such as CAR, PPARalpha and Ah receptor leading to promotion of rodent but probably not human hepatocarcinogenesis. Further studies on the different modes of action may help to avoid overestimation of the risk of liver tumor promotion.
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PMID:Promotion of hepatocarcinogenesis in humans and animal models. 1820 79

Peroxisome proliferator-activated receptor alpha (PPARalpha) ligands evoke a profound mitogenic response in rodent liver, and the aim of this study was to characterize the kinetics of induction of DNA synthesis. The CAR ligand, 1,4-bis[2-(3,5-dichoropyridyloxy)]benzene, caused induction of hepatocyte DNA synthesis within 48 h in 129S4/SvJae mice, but the potent PPARalpha ligand, ciprofibrate, induced hepatocyte DNA synthesis only after 3 or 4 days dosing; higher or lower doses did not hasten the DNA synthesis response. This contrasted with the rapid induction (24 h) reported by Styles et al., 1988, Carcinogenesis 9, 1647-1655. C57BL/6 and DBA/2J mice showed significant induction of DNA synthesis after 4, but not 2, days ciprofibrate treatment. Alderley Park and 129S4/SvJae mice dosed with methylclofenapate induced hepatocyte DNA synthesis at 4, but not 2, days after dosing and proved that inconsistency with prior work was not due to a difference in mouse strain or PPARalpha ligand. Ciprofibrate-induced liver DNA synthesis and growth was absent in PPARalpha-null mice and are PPARalpha dependent. In the Fisher344 rat, hepatocyte DNA synthesis was induced at 24 h after dosing, with a second peak at 48 h. Lobular localization of hepatocyte DNA synthesis showed preferential periportal induction of DNA synthesis in rat but panlobular zonation of hepatocyte DNA synthesis in mouse. These results characterize a markedly later hepatic induction of panlobular DNA synthesis by PPARalpha ligands in mouse, compared to rapid induction of periportal DNA synthesis in rat.
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PMID:Species-specific kinetics and zonation of hepatic DNA synthesis induced by ligands of PPARalpha. 1837 45

The development of cancer is associated with high oxidative stress and at the same time with immune system activation. Tumors develop efficient mechanisms of protection against the immune response, which allow them to escape the immune surveillance. Simultaneously, key events in the process of carcinogenesis are related to oxidative stress. The relationship between the two remains unknown. Novel understanding of oxidative stress shows that discrete changes of activities of certain enzyme systems such as NADPH oxidases or nitric oxide synthases may be more important than the overall balance of production and removal of reactive oxygen species. Such imbalance of nitric oxide and superoxide production could modify inflammation and immune regulation. We studied superoxide anion production (by lucigenin enhanced chemiluminescence - 5 microM), NADPH oxidase activity and nitric oxide synthase (NOS) dysfunction. In parallel mRNA expression of immunomodulatory markers such as FoxP3 (T regulatory cell marker), CCR6 (mucosal homing effector T cell marker) and CD85j (NK cell/CD8 T cell Ig-like MHC class I inhibitory receptor) was determined. Basal superoxide production and NADPH oxidase activity are increased in oral squamous cell carcinoma. Tumor superoxide production was inhibited by NADPH oxidase inhibitor apocynin and by NOS inhibitor L-NAME. This indicates, for the first time, that oral squamous cell carcinoma is characterized by dysregulated nitric oxide synthase, which apart from increased NADPH oxidase activity contributes to oxidative stress and may be related to the immuno-pathology of these tumors. Studied tumors were infiltrated by CCR6+, but showed lower expression of both CD85j and FoxP3 mRNA. Finally, the CD85j mRNA expression was inversely correlated to oxidative stress parameters. These preliminary studies indicate that tumor oxidative stress, related to NADPH oxidase activity and NOS activity could be related to immune responses to cancer, thus therapeutic modification of oxidative stress, which could include the correction of NOS dysfunction, could facilitate immune surveillance.
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PMID:NADPH oxidase and uncoupled nitric oxide synthase are major sources of reactive oxygen species in oral squamous cell carcinoma. Potential implications for immune regulation in high oxidative stress conditions. 1844 94

Patients with chronic gastro-oesophageal reflux disease experience the reflux of acid and bile into the distal oesophagus. The secondary bile salt sodium deoxycholate (NDC) is implicated in the induction of mucosal injury during reflux episodes. This study hypothesized that NDC damages DNA in oesophageal cells by an oxidative mechanism. In the oesophageal cell line HET1-A, increased production of nitric oxide (NO) was measured in NDC-treated cells. Protection from DNA strand breaks induced by NDC (10 microm) was observed in cells coincubated with the nitric oxide scavenger C-PTIO (p<0.012) or pre-incubated with the NO synthase inhibitor L-NAME (p<0.009) or the NFkappaB inhibitor, TPCK (p<0.036). Collectively these data implicate the involvement of NFkappaB and nitric oxide synthase in the DNA damage induced by NDC in oesophageal cells. In conclusion, NDC-driven NO production may play an important role in inducing DNA damage during episodes of gastro-oesophageal reflux and thereby contribute to reflux-related carcinogenesis.
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PMID:Sodium deoxycholate causes nitric oxide mediated DNA damage in oesophageal cells. 1915 54

Inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 are major inflammatory mediators. Nitric oxide (NO) produced by iNOS has been shown to have an important role in carcinogenesis. Recent studies have suggested that COX-2 expression also contributes to carcinogenesis, as well as tumor growth, invasion, and metastasis. COX-2 inhibitors such as celecoxib are widely recognized to have antitumor activity, but can cause adverse effects. We investigated possible relations between COX-2 and NO with the use of a human epidermoid carcinoma cell line, designated KB, in which overexpression of COX-2 protein was induced by gene transfer. We also assessed the possibility of using NOS inhibitor as an antitumor drug. We isolated a COX-2 transfected clone (KB/COX-2) and used a neomycin-transfected clone (KB/neo) as control. NG-nitro-L-arginine-methyl ester (L-NAME) was used as a NOS inhibitor, dihydrochloride (1400W) as an iNOS inhibitor, and celecoxib as a selective COX-2 inhibitor. All agents inhibited the cell growth of both clones to similar extents in a dose-dependent manner. Prostaglandin E2 (PGE2) production and COX-2 expression in KB/COX-2 were inhibited not only by celecoxib, but also by L-NAME and 1400W. The decreases in PGE2 production and COX-2 expression were most prominent with celecoxib and L-NAME. In vivo, L-NAME and celecoxib significantly inhibited the proliferation of KB/COX-2-xenografted tumors. Tumor weight was reduced by L-NAME (60.6% decrease), 1400W (38.0% decrease), and celecoxib (74.5% decrease) as compared with the control after 21 days of treatment. Immunohistochemically, xenografted tumors expressed COX-2, iNOS, and eNOS. Such expression was suppressed by treatment with L-NAME and celecoxib. These results suggest that L-NAME and celecoxib significantly inhibit the proliferation of murine squamous cell carcinoma in vivo. L-NAME as well as celecoxib might thus be useful for the design and development of new antitumor drugs.
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PMID:Antitumor effects of inhibitors of nitric oxide synthase or cyclooxygenase-2 on human KB carcinoma cells overexpressing COX-2. 2051 41

Registration of new plant protection products (e.g., herbicide, insecticide, or fungicide) requires comprehensive mammalian toxicity evaluation including carcinogenicity studies in two species. The outcome of the carcinogenicity testing has a significant bearing on the overall human health risk assessment of the substance and, consequently, approved uses for different crops across geographies. In order to understand the relevance of a specific tumor finding to human health, a systematic, transparent, and hypothesis-driven mode of action (MoA) investigation is, appropriately, an expectation by the regulatory agencies. Here, we describe a novel approach of prospectively generating the MoA data by implementing additional end points to the standard guideline toxicity studies with sulfoxaflor, a molecule in development. This proactive MoA approach results in a more robust integration of molecular with apical end points while minimizing animal use. Sulfoxaflor, a molecule targeting sap-feeding insects, induced liver effects (increased liver weight due to hepatocellular hypertrophy) in an initial palatability probe study for selecting doses for subsequent repeat-dose dietary studies. This finding triggered the inclusion of dose-response investigations of the potential key events for rodent liver carcinogenesis, concurrent with the hazard assessment studies. As predicted, sulfoxaflor induced liver tumors in rats and mice in the bioassays. The MoA data available by the time of the carcinogenicity finding supported the conclusion that the carcinogenic potential of sulfoxaflor was due to CAR/PXR nuclear receptor activation with subsequent hepatocellular proliferation. This MoA was not considered to be relevant to humans as sulfoxaflor is unlikely to induce hepatocellular proliferation in humans and therefore would not be a human liver carcinogen.
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PMID:An integrated approach for prospectively investigating a mode-of-action for rodent liver effects. 2360 86


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