Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0699790 (colon cancer)
28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inducible cyclooxygenase (COX-2) has been implicated in the processes of inflammation and carcinogenesis. Thus, the potential COX-2 inhibitors have been considered as anti-inflammatory or cancer chemopreventive agents. In this study, the methanolic extract of the cortex of Eugenia caryophyllata Thunberg (Myrtaceae) was found to potently inhibit the prostaglandin E(2) production in lipopolysaccharide (LPS)-activated mouse macrophage RAW264.7 cells (98.3% inhibition at the test concentration of 10 microg/ml). Further, hexane-soluble layer was the most active partition compared to ethyl acetate, n-butanol, and water-soluble parts. By bioassay-guided fractionation of hexane-soluble partition, eugenol was isolated and exhibited a significant inhibition of PGE(2) production (IC(50) = 0.37 microM). In addition, eugenol suppressed the cyclooxygenase-2 (COX-2) gene expression in LPS-stimulated mouse macrophage cells. On the line of COX-2 playing an important role in colon carcinogenesis further study was designed to investigate the effect of eugenol on the growth and COX-2 expression in HT-29 human colon cancer cells. Eugenol inhibited the proliferation of HT-29 cells and the mRNA expression of COX-2, but not COX-1. This result suggests that eugenol might be a plausible lead candidate for further developing the COX-2 inhibitor as an anti-inflammatory or cancer chemopreventive agent.
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PMID:Eugenol suppresses cyclooxygenase-2 expression in lipopolysaccharide-stimulated mouse macrophage RAW264.7 cells. 1275 41

The aim of the present study is to investigate the relation of cyclooxygenase (COX)-2 with liver metastasis. Pieces of human colon cancer xenograft were implanted orthotopically (CI), as well as intraperitoneally, and subcutaneously. Liver metastasis developed most frequently, and the COX-2 expression of both mRNA and protein of the tumors was the most dominant in the CI group. In contrast, the expression of COX-1 or vascular endothelial cell growth factor mRNAs had no significant differences among the groups. The intensity of COX-2 mRNA was negatively correlated with the apoptotic index. In conclusion, COX-2 plays an important role in organ-specific metastasis of the colon cancer.
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PMID:Orthotopic implantation of a colon cancer xenograft induces high expression of cyclooxygenase-2. 1276 32

Prostaglandin synthesis occurs via the coordinate action of a phospholipase that liberates arachidonic acid from membrane phospholipids and a cyclooxygenase (COX) that converts the free arachidonic acid to prostaglandins. Several lines of evidence suggest that prostaglandins play a role in carcinogenesis. Two isoforms of COX have been described. COX-2 is highly regulated and induced by inflammation while COX-1 is considered primarily a housekeeping form. The acute up-regulation of COX-2 by UV radiation suggests that it may contribute to photocarcinogenesis in the same way that COX-2 has recently been shown to contribute to colon cancer.
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PMID:The role of cyclooxygenase-2 in the pathogenesis of skin cancer. 1284 53

Since the synthesis of aspirin in 1897, aspirin-like or nonsteroidal antiinflammatory drugs (NSAIDs) have been the mainstay of therapy for rheumatoid arthritis. Although of diverse chemical structure, these drugs not only exhibit the same antipyretic, analgesic and antiinflammatory therapeutic actions, but they also manifest identical toxic actions on the gastric mucosa and the kidney. This indicated that a single pharmacological effect was responsible for the properties of NSAIDs, a theory that was confirmed by the epochal discovery by Vane in 1971, that inhibition of the enzyme-producing prostanoids (cyclooxygenase [COX]) produced both the therapeutic and side effects of aspirin-like drugs. However, at equivalent antiinflammatory doses, different NSAIDs exhibited different degrees of toxicity. The reason for this was resolved by the discovery that prostaglandins at sites of tissue damage were synthesized by an inducible COX (COX-2) formed by a gene distinct from that producing the constitutive enzyme (COX-1), responsible for the formation of prostaglandins that serve an essential physiological function. Modification of the structure of drugs showing a moderately selective effect on COX-2, and the elucidation of the crystal structure of both enzymes, has paved the way for the synthesis of NSAIDs that are highly selective for the inducible enzyme and which are, therefore, antiinflammatory without the typical side effects of the classical NSAIDs. The focus on COX-2 has also expanded our knowledge of the pathophysiological significance of prostanoids and raised the possibility of new uses for selective COX-2 inhibitors, for example, in colon cancer, premature labor and possibly Alzheimer's disease. However, the clinical effects of chronic administration of potent, selective COX-2 inhibitors must await the results of ongoing clinical trials.
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PMID:Nonsteroidal antiinflammatory agents. 1297 28

Metabolites of arachidonic acid participate in normal growth responses and in aberrant cellular growth and proliferation, including carcinogenesis. The key step in the conversion of free arachidonic acid to prostaglandins is catalyzed by the cyclooxygenase enzyme (COX). There are two COX enzymes, COX-1 and COX-2. COX-1 is expressed constitutively and is part of normal cell metabolic functions. COX-2, on the other hand, is induced and expressed in neoplastic growths. The connection between COX expression and carcinogenesis was first implicated in studies that demonstrated the efficacy of aspirin and non-steroidal anti-inflammatory drugs to reduce the relative risk of colon cancer and also promote tumor regression in both humans and animal models of colon cancer. Investigation of the molecular basis of these observations showed that high levels of COX-2 protein were present in both human and animal colorectal tumors. A variety of evidence gathered from epidemiological, whole animal, and cellular studies indicate that unregulated COX-2 expression is a rate-limiting step in tumorigenesis and also that the loss of regulation occurs early in carcinogenesis. The interest in the COX-2 enzyme is that specific inhibition of COX-2 could theoretically avoid the gastrointestinal and other complications observed with the use of nonspecific COX inhibitors (most NSAIDs) or COX-1 inhibitors. The mechanisms by which COX-2 inhibitors lead to decreased colon carcinogenesis are not fully understood but they involve an increase not only in COX-2 dependent but also in COX-2 independent mechanisms.
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PMID:COX-2 and colorectal cancer. 1452 4

Colorectal cancer (CRC) is the second leading cause of cancer death in the USA. Accumulation of beta-catenin protein is nearly ubiquitous in colon adenomas and cancers, presumably due to mutations in the APC or beta-catenin genes that inhibit proteasome-dependent degradation of beta-catenin protein. Substantial clinical, epidemiological, and animal evidence indicate that sulindac and other non-steroidal anti-inflammatory drugs (NSAIDs) prevent the development of CRC. The mechanisms by which sulindac exerts its potent growth inhibitory effects against colon tumor cells are incompletely understood, but down-regulation of beta-catenin has been suggested as one potential mechanism. The goal of this study was to determine the mechanism of beta-catenin protein down-regulation by sulindac metabolites. Treatment of human colon cancer cell lines with apoptotic concentrations of sulindac metabolites (sulindac sulfide, sulindac sulfone) induced a dose- and time-dependent inhibition of beta-catenin protein expression. Inhibition of proteasome activity with MG-132 partially blocked the ability of sulindac sulfide and sulindac sulfone to inhibit beta-catenin protein expression. Pretreatment with the caspase inhibitor z-VAD-fmk blocked morphological signs of apoptosis as well as caspase cleavage, and also partially prevented beta-catenin degradation by sulindac metabolites. These effects occurred in cells with bi-allelic APC mutation (SW480), with wild-type APC but mono-allelic beta-catenin mutation (HCT116) and in cells that lack expression of either COX-1 or -2 (HCT15). These results indicate that loss of beta-catenin protein induced by sulindac metabolites is COX independent and at least partially due to reactivation of beta-catenin proteasome degradation and partially a result of caspase activation during the process of apoptosis.
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PMID:Sulindac metabolites induce caspase- and proteasome-dependent degradation of beta-catenin protein in human colon cancer cells. 1455 7

Several epidemiological studies have supported the concept that high energy intake, obesity, and/or hyperinsulinemia are risk factors for colon cancer. Previously, it was shown that Zucker obese rats are more sensitive to chemically induced colon cancer than their lean counterparts. The present study investigated whether moderate (20-25%) dietary energy restriction (ER) would attenuate colon carcinogenesis in the Zucker obese rat model. Six-week-old Zucker obese (fa/fa) rats and lean (Fa/Fa) rats received s.c. injections of azoxymethane at a dose of 10 mg/kg body weight once weekly for 2 weeks. A week later, obese rats (n = 16) were assigned to an ER diet (Ob-ER group), based on a low-fat AIN-93G semisynthetic diet. The remaining obese and lean rats (n = 16 rats/group) were fed the low-fat diet ad libitum (Ob group and Ln group, respectively). All rats were euthanized after 8 weeks, and their colons were assessed for aberrant crypt foci (ACF; n = 8/group) or for the expression of transforming growth factor (TGF)-beta and cyclooxygenase (COX) isoforms at the protein and mRNA transcript levels (n = 8/group). Ob rats had a higher number of advanced ACF (crypt multiplicity >or=7) than Ln rats. Dietary ER significantly reduced the appearance of advanced ACF in Ob-ER rats without significantly affecting the blood insulin level or body weights. TGF-beta and COX isoforms were differentially expressed in the colonic mucosae of Ob and Ln rats. Dietary ER significantly reduced TGF-beta1/beta2 and COX-1/2 protein expression in obese rats. This study is the first to demonstrate that moderate ER attenuated TGF-beta and COX protein expression and the carcinogenic process in Zucker obese rats. These findings provide insights leading to the proposal that the mechanism(s) underlying the early events of colon carcinogenesis in Zucker obese rats may extend beyond the role of excessive body weight and hyperinsulinemia per se.
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PMID:Energy restriction reduces the number of advanced aberrant crypt foci and attenuates the expression of colonic transforming growth factor beta and cyclooxygenase isoforms in Zucker obese (fa/fa) rats. 1458 51

Nitric oxide (NO)-releasing aspirin (ASA), consisting of a traditional ASA molecule to which a NO-donating moiety is covalently bound, is a promising colon cancer chemopreventive agent. NO-ASA inhibits colon cancer cell growth more potently than ASA by inhibiting cell proliferation and enhancing cell killing. We examined in cultured human colon cancer cells the effect of NO-ASA on the beta-catenin/T-cell factor signaling pathway, nuclear factor-kappaB, and NO synthase 2 and on cyclooxygenase (COX) expression, all presumed to participate in colon carcinogenesis. Besides inhibiting cell growth, NO-ASA inhibited the beta-catenin/T-cell factor signaling pathway (IC(50), 1.1 microM), nuclear factor-kappaB DNA binding (IC(50), 7.5 microM), and NO synthase 2 expression (IC(50), 2 microM). Interestingly, NO-ASA induced COX-2 expression, although it had no effect on COX-1. COX-2 induction was accompanied by increased prostaglandin E(2) production. These effects occurred at NO-ASA concentrations below or near its IC(50) for cell growth (IC(50), 2-50 microM). The metabolism of NO-ASA by these cells is characterized by a rapid deacetylation step and the formation of a conjugate with glutathione. NO-ASA had no effect on intracellular cyclic GMP concentrations. We propose a model incorporating the pleiotropic effects of NO-ASA on cell signaling and postulate that collectively these effects may contribute to its strong chemopreventive effect.
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PMID:Growth inhibition of human colon cancer cells by nitric oxide (NO)-donating aspirin is associated with cyclooxygenase-2 induction and beta-catenin/T-cell factor signaling, nuclear factor-kappaB, and NO synthase 2 inhibition: implications for chemoprevention. 1463 77

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause damage in the upper gastrointestinal (GI) tract by impairing the ability of the mucosa to resist and respond to injury. Many of these effects of NSAIDs can be attributed to their ability to suppress mucosal prostaglandin synthesis. Selective inhibitors of cyclooxygenase (COX)-2 are less likely to disrupt mucosal defence and do not interfere with platelet aggregation. Thus, their use is associated with a reduced incidence of serious GI adverse events; however, a significant risk of such events still persists. At least in animal models, selective COX-2 inhibitors interfere with ulcer healing to the same extent as conventional NSAIDs. In contrast, COX-inhibiting nitric oxide donors (CINODs) produce anti-inflammatory and analgesic effects comparable or superior to those of NSAIDs, but with greatly reduced GI toxicity. Unlike NSAIDs and selective COX-2 inhibitors, CINODs do not interfere with ulcer healing. Moreover, because CINODs suppress the activity of both COX-1 and COX-2, they do not share with selective COX-2 inhibitors the lack of cardioprotection afforded by significant suppression of platelet aggregation. Because of their safety profile, CINODs may be particularly useful for long term prevention applications, such as for colon cancer, cardiovascular disease and Alzheimer's disease.
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PMID:Mechanisms of nonsteroidal anti-inflammatory drug-induced gastrointestinal injury and repair: a window of opportunity for cyclooxygenase-inhibiting nitric oxide donors. 1505 99

Aberrant arachidonic acid metabolism is involved in the inflammatory and carcinogenic processes. In this study, we investigated the effects of curcumin, a naturally occurring chemopreventive agent, and related beta-diketone derivatives on the release of arachidonic acid and its metabolites in the murine macrophage RAW264.7 cells and in HT-29 human colon cancer cells. We also examined their effects on the catalytic activities and protein levels of related enzymes: cytosolic phospholipase A(2) (cPLA(2)), cyclooxygenases (COX) as well as 5-lipoxygenase (5-LOX). At 10 micro M, dibenzoylmethane (DBM), trimethoxydibenzoylmethane (TDM), tetrahydrocurcumin (THC) and curcumin effectively inhibited the release of arachidonic acid and its metabolites in lipopolysaccharide (LPS)-stimulated RAW cells and A23187-stimulated HT-29 cells. Inhibition of phosphorylation of cPLA(2), the activation process of this enzyme, rather than direct inhibition of cPLA(2) activity appears to be involved in the effect of curcumin. All the curcuminoids (10 micro M) potently inhibited the formation of prostaglandin E(2) (PGE(2)) in LPS-stimulated RAW cells. Curcumin (20 micro M) significantly inhibited LPS-induced COX-2 expression; this effect, rather than the catalytic inhibition of COX, may contribute to the decreased PGE(2) formation. Without LPS-stimulation, however, curcumin increased the COX-2 level in the macrophage cells. Studies with isolated ovine COX-1 and COX-2 enzymes showed that the curcuminoids had significantly higher inhibitory effects on the peroxidase activity of COX-1 than that of COX-2. Curcumin and THC potently inhibited the activity of human recombinant 5-LOX, showing estimated IC(50) values of 0.7 and 3 micro M, respectively. The results suggest that curcumin affects arachidonic acid metabolism by blocking the phosphorylation of cPLA(2), decreasing the expression of COX-2 and inhibiting the catalytic activities of 5-LOX. These activities may contribute to the anti-inflammatory and anticarcinogenic actions of curcumin and its analogs.
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PMID:Modulation of arachidonic acid metabolism by curcumin and related beta-diketone derivatives: effects on cytosolic phospholipase A(2), cyclooxygenases and 5-lipoxygenase. 1507 46


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