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)

The present study investigates the effects of gastrin-17 on human colon cancer HT-29 cells to examine whether gastrin receptor (CCK-2), cyclooxygenase (COX-1, COX-2) isoforms and prostaglandin receptor pathways interact to control cell growth. Reverse transcription (RT)-polymerase chain reaction (PCR) analysis demonstrated that HT-29 cells are endowed with the naive expression of CCK-2 receptor (short splice variant), COX-1, COX-2 and prostaglandin EP(4) receptor, but not gastrin. Gastrin-17 significantly promoted cell growth and DNA synthesis. Both these stimulating effects were abolished by L-365,260 or GV150013 (CCK-2 receptor antagonists), but were unaffected by SC-560 (COX-1 inhibitor). L-745,337 (COX-2 inhibitor) or AH-23848B (EP(4) receptor antagonist) partly reversed gastrin-17-induced cell growth, while they fully antagonized the enhancing action on DNA synthesis. HT-29 cells responded to gastrin-17 with a significant increase in prostaglandin E(2) release. This enhancing effect was completely counteracted by L-365,260, GV150013 or L-745,337, while it was insensitive to cell incubation with SC-560. Exposure of HT-29 cells to gastrin-17 was followed by an increased phosphorylation of both extracellular regulated kinases (ERK-1/ERK-2) and Akt. Moreover, gastrin-17 enhanced the transcriptional activity of COX-2 gene promoter and stimulated COX-2 expression. These latter effects were antagonized by L-365,260 or GV150013, and could be blocked also by PD98059 (inhibitor of ERK-1/ERK-2 phosphorylation) or wortmannin (inhibitor of phosphatidylinositol 3-kinase). Analogously, gastrin-17-induced prostaglandin E(2) release was prevented by PD98059 or wortmannin. The present results suggest that (a) in human colon cancer cells endowed with CCK-2 receptors, gastrin-17 is able to enhance the transcriptional activity of COX-2 gene through the activation of ERK-1/ERK-2- and phosphatidylinositol 3-kinase/Akt-dependent pathways; (b) these stimulant actions lead to downstream increments of COX-2 expression, followed by prostaglandin E(2) production and EP(4) receptor activation; (c) the recruitment of COX-2/prostaglandin pathways contributes to the growth-promoting actions exerted by gastrin-17.
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PMID:Gastrin promotes human colon cancer cell growth via CCK-2 receptor-mediated cyclooxygenase-2 induction and prostaglandin E2 production. 1565 24

Cyclooxygenase and human tumor cell growth inhibitory extracts of horseradish (Armoracia rusticana) and wasabi (Wasabia japonica) rhizomes upon purification yielded active compounds 1-3 from horseradish and 4 and 5 from wasabi rhizomes. Spectroscopic analyses confirmed the identities of these active compounds as plastoquinone-9 (1), 6-O-acyl-beta-d-glucosyl-beta-sitosterol (2), 1,2-dilinolenoyl-3-galactosylglycerol (3), linolenoyloleoyl-3-beta-galactosylglycerol (4), and 1,2-dipalmitoyl-3-beta-galactosylglycerol (5). 3-Acyl-sitosterols, sinigrin, gluconasturtiin, and phosphatidylcholines isolated from horseradish and alpha-tocopherol and ubiquinone-10 from wasabi rhizomes isolated were inactive in our assays. At a concentration of 60 microg/mL, compounds 1 and 2 selectively inhibited COX-1 enzyme by 28 and 32%, respectively. Compounds 3, 4, and 5 gave 75, 42, and 47% inhibition of COX-1 enzyme, respectively, at a concentration of 250 microg/mL. In a dose response study, compound 3 inhibited the proliferation of colon cancer cells (HCT-116) by 21.9, 42.9, 51.2, and 68.4% and lung cancer cells (NCI-H460) by 30, 39, 44, and 71% at concentrations of 7.5, 15, 30, and 60 microg/mL, respectively. At a concentration of 60 microg/mL, compound 4 inhibited the growth of colon, lung, and stomach cancer cells by 28, 17, and 44%, respectively. This is the first report of the COX-1 enzyme and cancer cell growth inhibitory monogalactosyl diacylglycerides from wasabi and horseradish rhizomes.
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PMID:Tumor cell proliferation and cyclooxygenase inhibitory constituents in horseradish (Armoracia rusticana) and Wasabi (Wasabia japonica). 1574 20

Clear (CleA) and cloudy (CloA) apple juices containing different amounts of analyzed procyanidins and pectin were investigated for preventive effects of colon cancer and underlying molecular mechanisms in F344 rats given intraperitoneal injections of 1,2-dimethylhydrazine (DMH; 20 mg/kg body wt) once a week for 4 weeks. Rats received either water (Cont), CleA or CloA (ad libitum) for 7 weeks starting 1 week before the first DMH injection. CloA inhibited DMH induced genotoxic damage in mucosa cells of the distal colon compared with Cont as investigated by single-cell microgel electrophoresis assay. The mean tail intensity in mucosa cells of DMH-treated controls (Cont/DMH: 6.1+/-0.9%) was significantly reduced by CloA (2.4+/-0.8%; P<0.01) but not by CleA intervention (4.1+/-1.2%; P>0.05). The crypt cell proliferation index induced by DMH (Cont/NaCl: 10.0+/-0.7%; Cont/DMH: 19.9+/-1.0%; P<0.001) was significantly decreased by CleA (15.7+/-0.7%; P<0.001) and CloA intervention (11.9+/-0.4%; P<0.001). CloA but not CleA significantly reduced the number of large aberrant crypt foci (ACF) consisting of more than four aberrant crypts (AC) (Cont/DMH: 37.4+/-5.4; CleA/DMH: 32.8+/-4.4, P>0.05; CloA/DMH: 18.8+/-2.5 ACF; P<0.05) and the overall mean ACF size in the distal colon (Cont/DMH: 2.31+/-0.09; CleA/DMH: 2.27+/-0.05; CloA/DMH: 2.04+/-0.03 AC/ACF; P<0.05). After treatment with DMH and/or apple juices there were no changes in transcript levels of colonic cyclooxygenase isoforms (COX-1, COX-2) or glutathione-associated enzymes (GST-M2, gamma-GCS, GST-P), the splenocyte natural killer cell activity and plasma antioxidant status. However, CloA but not CleA prevented the DMH-induced reduction of splenocyte CD4/CD8 (T-helper cells to cytotoxic lymphocytes) ratio. Since both formulations contained comparable concentrations and types of monomeric polyphenols, complex polyphenols or non-polyphenolic compounds, such as pectin might be responsible for the stronger cancer-preventive effect by CloA.
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PMID:Cloudy apple juice decreases DNA damage, hyperproliferation and aberrant crypt foci development in the distal colon of DMH-initiated rats. 1580 99

A 4-stage colon simulator and a cell culture-based human intestinal epithelial function model were combined to study the effects of a soluble fiber, polydextrose (PDX), on intestinal microbes and mucosal functions relevant to the risk of colon cancer. We observed sustained degradation of PDX throughout the different stages of the model. The fermentation was characterized by gradual degradation of PDX, production of short-chain fatty acids, and no increasing in putrefactive markers. We observed less marked effects in the microbial densities. When we applied colon fermentation metabolites obtained from the simulators with PDX to Caco-2 colon cancer cell line, a significant dose-dependent decreasing effect on cyclooxygenase-2 (COX-2) and an increasing effect on COX-3 expression levels were observed. PDX concentration appeared not to have effect on the expression levels of COX-1. Overexpression of COX-2 and decreased expression of COX-1 have been suggested to be characteristics of colon cancer. The exact physiological role of COX-3, an intron-retaining splice variant of COX-1, is not known, but it is suspected to play a role in transcriptional regulation of COX-1 and COX-2. In vitro modulation of COX expression by colon microbial fermentation products of polydextrose offers an interesting starting point for further studies on possible risk-decreasing effect of PDX on the development of colon cancer.
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PMID:In vitro effects on polydextrose by colonic bacteria and caco-2 cell cyclooxygenase gene expression. 1609 Oct 9

Glycine-extended gastrin (G-Gly) is an end product of processing of the progastrin precursor peptide that has a different spectrum of activity to amidated gastrin. G-Gly promotes cell proliferation in normal and malignant colonic epithelium but the mechanisms responsible are poorly understood. Prostaglandins produced by the cyclo-oxygenase (COX) enzymes have been implicated as downstream mediators of several growth factors, and COX inhibitors such as non-steroidal anti-inflammatory drugs inhibit the proliferation and invasiveness of colonic cancer and reduce the incidence of colon cancer. We have examined the mechanisms of the actions of G-Gly in HT-29 colon cancer cells. G-Gly induced a dose-dependent increase in cell proliferation that was insensitive to inhibition of either COX-1 or COX-2, but was abolished by inhibition of the p38 MAP kinase, ERK and NF-kappaB pathways. G-Gly did not increase prostaglandin E2 production. Celecoxib induced apoptosis and reduced viable cell numbers in a COX-independent manner. G-Gly significantly reduced serum-starvation and celecoxib-induced apoptosis and this effect was also blocked by inhibition of the p38 MAP kinase, ERK and NF-kappaB pathways. Stimulation of HT-29 cells with G-Gly led to a rapid increase in ERK and p38 MAP kinase phosphorylation and increased nuclear translocation of active NF-kappaB. Activation of NF-kappaB was independent of ERK and p38 MAP kinase. G-Gly stimulates proliferation and inhibits apoptosis in colon cancer cells via COX-independent and ERK-, p38 MAP kinase-, and NF-kappaB-dependant pathways. Locally and systemically produced G-Gly may be important in reducing the beneficial effects of chemopreventative agents in colon cancer.
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PMID:Glycine-extended gastrin stimulates proliferation and inhibits apoptosis in colon cancer cells via cyclo-oxygenase-independent pathways. 1616 10

While brown rice is a staple dietary constituent in Asia, rice consumed in the Western world is generally white, obtained from brown rice by removal of the bran. Rice bran contains the flavone tricin, which has been shown to inhibit colon cancer cell growth. We tested the hypothesis that tricin interferes with adenoma formation in the Apc(Min) mouse. Mice received tricin (0.2%) in their American Institute of Nutrition 93G diet throughout their postweaning life span (4-18 weeks). Consumption of tricin reduced numbers of intestinal adenomas by 33% (P < 0.05) compared with mice on control diet. We explored whether tricin may exert its effect via inhibition of cyclooxygenase (COX) enzymes. Its effect on COX activity was assessed in purified enzyme preparations in vitro and its ability to reduce prostaglandin E(2) (PGE(2)) levels in human colon-derived human colon epithelial cell (HCEC) and HCA-7 cells in vitro and in Apc(Min) mice in vivo. Tricin inhibited activity of purified COX-1 and COX-2 enzyme preparations with IC(50) values of approximately 1 micromol/L. At 5 micromol/L, it reduced PGE(2) production in HCEC or HCA-7 cells by 36% (P < 0.01) and 35% (P < 0.05), respectively. COX-2 expression was reduced by tricin weakly in HCEC and unaffected in HCA-7 cells. PGE(2) levels in the small intestinal mucosa and blood of Apc(Min) mice that had received tricin were reduced by 34% (P < 0.01) and 40% (P < 0.05), respectively, compared with control mice. The results suggest that tricin should be further evaluated as a putative colorectal cancer chemopreventive agent.
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PMID:The rice bran constituent tricin potently inhibits cyclooxygenase enzymes and interferes with intestinal carcinogenesis in ApcMin mice. 1617 19

Carcinoma of the colon or rectum represents one of the most common malignancies worldwide with a higher prevalence in industrialized regions. Epidemiologic studies of individuals taking non-steroidal anti-inflammatory drugs (NSAIDs) have shown a significant reduction in colorectal cancer (CRC) mortality compared to those individuals not receiving these agents. NSAIDs inhibit the enzymatic activity of both isoforms of cyclooxygenase (COX-1 and COX-2), while COX-2-selective inhibitors have shown some efficacy in reducing polyp formation. COX-2-derived bioactive lipids, including the primary prostaglandin (PG) generated in colorectal tumors, PGE(2), are known to stimulate cell migration, proliferation and tumor-associated neovascularization while inhibiting cell death. Here we briefly review the role of NSAIDs in preventing CRC, as well as the proposed mechanism by which a COX-2-derived PG, PGE(2), promotes colon cancer.
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PMID:Mechanisms for the prevention of gastrointestinal cancer: the role of prostaglandin E2. 1621 Aug 74

Platelets are rich sources of growth factors and enzymes that are implicated in a number of diseases including obesity, atherosclerosis, heart disease, syndrome X, liver and kidney diseases and certain types of cancers. In this research we investigated, if platelets in Zucker obese rats differ from their lean counterparts with respect to the levels of TGF-beta and COX isoforms, implicated in the pathogenesis of chronic diseases. In addition, we investigated if energy intake of the animals affects the platelet physiology. Platelets were isolated from obese and lean rats bearing preneoplastic lesions in their colon. Prior to platelet isolation these rats were fed either ad libitum (Ob or Ln) or energy restricted (Ob-ER or Ln-ER) diets for 8 weeks (n = 8/group). The levels of TGF-beta1/-beta2 and COX-1/-2 proteins in platelets were analyzed by Western blot. The platelets of the Ob rats had significantly higher levels of TGF-beta1, COX-1/-2 (p < 0.001) than did the platelets of the Ln rats and were not affected by moderate energy restriction. There were no significant differences in the protein expression of platelet TGF-beta2 among any of the groups. These results demonstrate that cytokines and candidates playing a role in the pathogenesis of chronic diseases, such as TGF-beta1 and COX-1/-2, are over-expressed in platelets of Zucker obese rats by comparison to their lean counterparts. These findings also demonstrate that the genotype of the animals exerts a significant effect on the biochemical composition of the platelets and could contribute to the pathogenesis of colon cancer and other metabolic abnormalities associated with obesity.
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PMID:Obese state leads to elevated levels of TGF-beta and COX isoforms in platelets of Zucker rats. 1647 87

Since the discovery of COX-2, a second subtype of cyclooxygenase, selective inhibitors or "coxibs" were developed with the idea that this isoform was inducible at the site of inflammation whereas COX-1 was expressed constitutively in several tissues including gastric epithelium. This new class of non steroidal anti-inflammatory agents was though to be safer for ulcerations of the gastroinstestinal mucosa observed with non selective COX-2 inhibitors. Nevertheless, at the end of September 2004, Merck & Co announced the voluntary withdrawal of rofecoxib (Vioxx) worldwide because of an increased risk of cardiovascular events. This decision raised serious concerns about safety of selective COX-2 inhibitors which are actively marketed today, and the ones currently under development. The mechanism of this cardiovascular toxicity could lie in the inhibition of COX-2 itself, and thus be a class effect. On the other hand, these cardiovascular side effects could be limited on rofecoxib and be dependent on its chemical and/or pharmacological own properties. This hypothesis is undermined by the unexpected findings of one colon cancer study which has shown that celecoxib might also increase the chance of heart attack and stroke in some patients. In this review, we compared the different coxibs marketed to date on the basis of their clinical, pharmacological and chemical properties with the aim of providing some clues in the understanding of their potential or revealed "cardiovascular effects".
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PMID:Coxibs and cardiovascular side-effects: from light to shadow. 1653 64

The antioxidant ferulic and caffeic acid phenolics are ubiquitous in plants and abundant in fruits and vegetables. We have synthesized a series of ferulic and caffeic acid esters and tested for tumor cell proliferation, cyclooxygenase enzymes (COX-1 and -2) and lipid peroxidation inhibitory activities in vitro. In the tumor cell proliferation assay, some of these esters showed excellent growth inhibition of colon cancer cells. Among the phenolics esters assayed, compounds 10 (C12-caffeate), 11 (C16-caffeate), 21 (C8-ferulate), and 23 (C12-ferulate) showed strong growth inhibition with IC50 values of 16.55, 13.46, 18.67, and 7.57 microg/mL in a breast cancer cell line; 9.65, 7.45, 17.05, and 4.35 microg/ mL in a lung cancer cell line; 5.78, 3.5, 4.29, and 2.46 microg/mL in a colon cancer cell line; 12.04, 12.21, 14.63, and 8.09 microg/ mL in a central nervous system cancer cell line; and 8.62, 7.76, 11.0, and 5.37 in a gastric cancer cell line. In COX enzyme inhibitory assays, ferulic and caffeic acid esters significantly inhibited both COX-1 and COX-2 enzymes. Caffeates 5-10 (C4-C12), inhibited COX-1 enzyme between 50% and 90% and COX-2 enzyme by about 70%, whereas ferulates 15-21 (C3-C8) inhibited COX-1 and COX-2 enzymes by 85-95% 25 microg/mL. Long-chain caffeates 11-14 (C16-C22) and short-chain ferulates 15-20 (C3-C5) were the most active in lipid peroxidation inhibition and showed 60-70% activity at 5 microg/mL concentration.
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PMID:Impact of alkyl esters of caffeic and ferulic acids on tumor cell proliferation, cyclooxygenase enzyme, and lipid peroxidation. 1684 20


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