Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arachidonic acid is metabolized to prostaglandin H(2) (PGH(2)) by cyclooxygenase (COX). COX-2, the inducible COX isozyme, has a key role in intestinal polyposis. Among the metabolites of PGH(2), PGE(2) is implicated in tumorigenesis because its level is markedly elevated in tissues of intestinal adenoma and colon cancer. Here we show that homozygous deletion of the gene encoding a cell-surface receptor of PGE(2), EP2, causes decreases in number and size of intestinal polyps in Apc(Delta 716) mice (a mouse model for human familial adenomatous polyposis). This effect is similar to that of COX-2 gene disruption. We also show that COX-2 expression is boosted by PGE(2) through the EP2 receptor via a positive feedback loop. Homozygous gene knockout for other PGE(2) receptors, EP1 or EP3, did not affect intestinal polyp formation in Apc(Delta 716) mice. We conclude that EP2 is the major receptor mediating the PGE2 signal generated by COX-2 upregulation in intestinal polyposis, and that increased cellular cAMP stimulates expression of more COX-2 and vascular endothelial growth factor in the polyp stroma.
 ...
PMID:Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc(Delta 716) knockout mice. 1153 9

Curcumin, a major yellow pigment and active component of turmeric, has been shown to possess anti-inflammatory and anti-cancer activities. Cyclooxygenase (COX)-2 plays an important role in colon carcinogenesis. To investigate the effect of curcumin on COX-2 expression, we treated HT-29 human colon cancer cells with various concentrations of curcumin. Curcumin inhibited the cell growth of HT-29 cells in a concentration- and time-dependent manner. Curcumin markedly inhibited the mRNA and protein expression of COX-2, but not COX-1. These data suggest that a non-toxic concentration of curcumin has a significant effect on the in vitro growth of HT-29 cells, specifically inhibits COX-2 expression, and may have value as a safe chemopreventive agent for colon cancer.
 ...
PMID:Specific inhibition of cyclooxygenase-2 (COX-2) expression by dietary curcumin in HT-29 human colon cancer cells. 1156 84

It has been proposed that Cyclooxygenase (COX)-2 inhibitors may be able to enhance the effects of chemotherapeutic or radiation treatment; however, currently few studies have been reported that define the radiation-enhancing effect of COX-2 inhibitors. We conducted in vitro radiation survival experiments using rat intestinal epithelial cells which were stably transfected with COX-2 cDNA in the sense (RIE-S) and antisense (RIE-AS) orientations to investigate the potential radiosensitizing effect of the selective COX-2 inhibitor, NS-398. Apoptosis was measured using 7-aminoactinomycin-D with flow cytometry to investigate underlying mechanisms for the effect of NS-398 on radiosensitivity. The same experiments were repeated with NCI-H460 human lung cancer cells, which express COX-2 constitutively, and HCT-116 human colon cancer cells, which lack COX-2 expression. In vivo tumor growth delay assays were also performed with tumors formed by H460 and HCT-116 cells. No difference was observed in the intrinsic radiation sensitivity of RIE-S and RIE-AS cells exposed to radiation alone. However, 150-400 microM of NS-398 enhanced radiosensitivity in a concentration-dependent manner in RIE-S cells with dose enhancement ratios of 1.2-1.9 at a surviving fraction of 0.25. However, this effect was not shown in RIE-AS cells. NS-398 enhanced radiosensitivity in H460 cells with a dose enhancement ratio of 1.8 but protected HCT-116 cells from the effects of radiation. Radiation-induced apoptosis was enhanced by NS-398 in RIE-S and H460 cells but not in RIE-AS and HCT-116 cells. Additionally, this radiation-enhancing effect in RIE-S cells seemed to be attributable to some mechanisms other than the reversal of radioresistance induced by COX-2. NS-398 (36 mg/kg) enhanced the effect of radiation on H460 tumors in vivo by an enhancement factor of 2.5; however, it did not enhance the radiosensitivity of HCT-116 tumors (enhancement factor = 1.04). These in vitro and in vivo results suggest that selective COX-2 inhibitors enhance the effect of radiation on tumors that express COX-2 but not on COX-2-lacking tumors. This effect may be attributable to enhancement of radiation-induced apoptosis. Thus, selective COX-2 inhibitors may have potential as radiosensitizers for treatment of human cancers.
 ...
PMID:A selective cyclooxygenase-2 inhibitor, NS-398, enhances the effect of radiation in vitro and in vivo preferentially on the cells that express cyclooxygenase-2. 1159 87

1. Nonsteroidal anti-inflammatory drug (NSAID) usage is associated with gastrointestinal inflammatory damage and aggravation of gut inflammatory conditions. NSAIDs also exert a preventive effect against colon cancer that seems to be due to increased colon cell apoptosis. NSAIDs have been shown to modulate the release of colony stimulating factors (CSFs) in some cells. In the present study we analysed the effect of these drugs on secretion of CSFs and apoptosis in human colon epithelial cells (HT-29). 2. HT-29 cells secreted bioactive levels of GM-CSF, G-CSF and M-CSF when stimulated with IL-1ss and TNF-alpha, and diclofenac (10(-7)-10(-4) M), indomethacin (10(-7)-10(-4) M) and sodium salicylate (10(-5)-10(-2) M) induced concentration-dependent increases in GM-CSF secretion. 3. Reduced secretion of G-CSF and M-CSF and increased cell apoptosis were observed with the highest concentrations of these non-selective NSAIDs. 4. No changes in any CSF release or HT-29 cell apoptosis were detected in the presence of the COX-2 selective inhibitor DFP (10(-7)-10(-4) M). 5. Neither the exogenous addition of CSFs nor the blockade of secreted CSFs modified apoptosis in HT-29 cells stimulated with cytokines and/or NSAIDs. 6. These results suggest that colon epithelial cells can contribute to local inflammatory responses by releasing CSFs and thus extend the life span of local leukocytes. Modulation of CSF levels by non-selective NSAIDs may be involved in the pro-inflammatory effects of these agents in the gut.
 ...
PMID:Relationship between endogenous colony stimulating factors and apoptosis in human colon cancer cells: role of cyclo-oxygenase inhibitors. 1170 43

The effects of green and black tea polyphenols on cyclooxygenase (COX)- and lipoxygenase (LOX)-dependent arachidonic acid metabolism in normal human colon mucosa and colon cancers were investigated. At a concentration of 30 microg/mL, (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), and (-)-epicatechin-3-gallate (ECG) from green tea and theaflavins from black tea inhibited LOX-dependent activity by 30-75%. The formation of 5-, 12-, and 15-LOX metabolites was inhibited to a similar extent. Tea polyphenols also inhibited COX-dependent arachidonic acid metabolism in microsomes from normal colon mucosa, with ECG showing the strongest inhibition. The formation of thromboxane (TBX) and 12-hydroxyheptadecatrienoic acid (HHT) was decreased to a greater extent than other metabolites. The inhibitory effects of tea polyphenols on COX activity, however, were less pronounced in tumor microsomes than in normal colon mucosal microsomes. Theaflavins strongly inhibited the formation of TBX and HHT, but increased the production of prostaglandin E(2) (PGE(2)) in tumor microsomes. The enhancing effect of theaflavins on PGE(2) production was related to the COX-2 level in the microsomes. Although theaflavin inhibited ovine COX-2, its activity in the formation of PGE(2) was stimulated by theaflavin when ovine COX-2 was mixed with microsomes, suggesting that theaflavin affects the interaction of COX-2 with other microsomal factors (e.g. PGE synthase). The present results indicate that tea polyphenols can affect arachidonic acid metabolism in human colon mucosa and colon tumors, and this action may alter the risk for colon cancer in humans.
 ...
PMID:Effects of purified green and black tea polyphenols on cyclooxygenase- and lipoxygenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues. 1170 50

Colorectal cancer is becoming increasingly common in Asian countries and still remains the second leading cause of cancer deaths in the United States. Efforts to prevent colon cancer have targeted early detection through screening and chemoprevention. For the last ten years our laboratory has utilized an in vivo screening assay for the testing of potential cancer preventives for colon cancer. We have conducted investigations on over 150 compounds including many with botanical or herbal origins. As part of our program on natural products we have examined a number of herbal and botanical products in the aberrant crypt foci (ACF) assay including Korean red ginseng powder, green tea catechins, curcumin from the Indian culinary spice, tumeric, compounds from garlic and onion, resveratrol from red grapes, among others. In the ginseng experiments groups of 10 F344 rats were fed ginseng powder at a dose of 0.5 g/kg or 2 mg/kg for 5 weeks. During weeks 2 and 3 rats were injected with 10 mg/kg azoxymethane to induce ACF. Controls (n=10) did not receive azoxymethane (AOM). Rats were killed by CO2 overdose and ACF counted in the rat colon. In 8 week post-initiation experiments ginseng powder inhibited the progression of established ACF, indicating a cytostatic effect. This may be due to an anti-inflammatory effect. There is a body of literature that suggests that compounds in wine, tumeric, and tea inhibit cyclooxygenases, thus reducing prostaglandin-mediated effects on the colon. As colon tumors have been shown to highly express COX-2 protein, and given, that many NSAID drugs also suppress COX-1, it is tempting to speculate that herbal products that inhibit one or both forms of the COX enzyme will be effective agents for the prevention of cancer in man.
 ...
PMID:Colon cancer chemoprevention with ginseng and other botanicals. 1174 82

Prostaglandins (PGs), bioactive lipid molecules produced by cyclooxygenase enzymes (COX-1 and COX-2), have diverse biological activities, including growth-promoting actions on gastrointestinal mucosa. They are also implicated in the growth of colonic polyps and cancers. However, the precise mechanisms of these trophic actions of PGs remain unclear. As activation of the epidermal growth factor receptor (EGFR) triggers mitogenic signaling in gastrointestinal mucosa, and its expression is also upregulated in colonic cancers and most neoplasms, we investigated whether PGs transactivate EGFR. Here we provide evidence that prostaglandin E2 (PGE2) rapidly phosphorylates EGFR and triggers the extracellular signal-regulated kinase 2 (ERK2)--mitogenic signaling pathway in normal gastric epithelial (RGM1) and colon cancer (Caco-2, LoVo and HT-29) cell lines. Inactivation of EGFR kinase with selective inhibitors significantly reduces PGE2-induced ERK2 activation, c-fos mRNA expression and cell proliferation. Inhibition of matrix metalloproteinases (MMPs), transforming growth factor-alpha (TGF-alpha) or c-Src blocked PGE2-mediated EGFR transactivation and downstream signaling indicating that PGE2-induced EGFR transactivation involves signaling transduced via TGF-alpha, an EGFR ligand, likely released by c-Src-activated MMP(s). Our findings that PGE2 transactivates EGFR reveal a previously unknown mechanism by which PGE2 mediates trophic actions resulting in gastric and intestinal hypertrophy as well as growth of colonic polyps and cancers.
 ...
PMID:Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. 1187 1

Apoptosis plays a central role in tumor development and it has been hypothesized that lack/failure of apoptosis leads to the development of tumors, including colon tumors. Thus, induction of apoptosis in tumor cells is an effective approach to the regulation of tumor growth. It has been shown by us and other investigators that various chemopreventive agents induce apoptosis and inhibit tumor growth. Identification of agents or combinations of agents that induce tumor cell apoptosis guides the development of novel agents for colon cancer treatment. Experiments were designed to assess the effectiveness of lovastatin, a 3-hydroxy-3-methyl glutaryl-CoA reductase inhibitor, and celecoxib a cyclooxygenase-2 inhibitor, individually or in combination on the induction of apoptosis in human HT-29 colon cancer cells. In addition, we studied the modulatory effect of lovastatin and celecoxib on lamin B levels, caspase-3 activity and expression in relationship to apoptosis in colon cancer cell lines. HT-29 cells exposed to various subtoxic levels of lovastatin or celecoxib or a combination of both were analyzed for apoptosis (by DAPI method), caspase-3 expression (immunoblot analysis) and caspase-3 activity (fluorimetric method). We found that: i) pretreatment with lovastatin (5-30 microM) induces apoptosis in HT-29 cells significantly only at high concentrations (> or = 20 microM) but not at low dose levels; ii) similarly, pretreatment with celecoxib produced apoptosis in colon cancer cells at high concentrations only (> or = 75 microM); iii) caspase-3 protein expression was moderately altered by the treatment with lovastatin or celecoxib at lower concentrations; however, a significant increase (1.6 to 4-fold) in caspase-3 expression and activity was found in HT-29 cells exposed with 20-25 microM lovastatin and/or 5-125 microM celecoxib and iv) importantly, in tumor cells exposed to low doses of (5 or 10 microM) lovastatin, combined with 25-75 microM of celecoxib, apoptosis induction rose 2.5 to 10-fold, caspase-3 expression was 2.3 to 8-fold higher, and enzyme activities were 1.5 to 5.5-fold elevated. This effect was highly synergistic and dose-dependent. Lamin B levels were significantly increased in a dose-dependent manner in cells treated with lovastatin but no such effect was observed with celecoxib. These results indicate that agents with different modes of action when applied in combinations will induce apoptosis synergistically by enhancing caspase-3 activities. These findings further support the hypothesis that HMGCo-R and COX-2 activities play important roles in apoptosis and regulation of apoptosis by selective agents such as lovastatin and celecoxib would provide effective strategies for the prevention of colon cancer.
 ...
PMID:Lamin B, caspase-3 activity, and apoptosis induction by a combination of HMG-CoA reductase inhibitor and COX-2 inhibitors: a novel approach in developing effective chemopreventive regimens. 1189 21

Cyclooxygenase (COX) is the crucial enzyme for synthesis of prostaglandins and occurs in two isoforms COX-1 and COX-2. Whilst COX-1 is constantly expressed in the gastrointestinal tract in large quantities and probably maintains mucosal integrity through constant generation of prostaglandins, COX-2 is induced principally during inflammation. In early gastric cancer and in intestinal metaplasia the expression of COX-2 in patients infected by Helicobacter pylori is increased in intestinal type compared to diffuse type gastric cancer and in intestinal metaplasia. In tumours of mixed type, COX-2 is also increased in the intestinal component compared to the diffuse component. Whilst there has been success of COX-2 inhibition for chemoprevention in colon cancer, a similar role in gastric cancer needs to be carefully assessed in the light of reported adverse effects and whether the precancerous condition, intestinal metaplasia, can truly regress.
 ...
PMID:Cyclooxygenase-2 expression in early gastric cancer, intestinal metaplasia and Helicobacter pylori infection. 1194 46

Platelets are implicated in the pathogenesis of various chronic diseases including cancer. The main objective of the present study was to determine if dietary fish oil and piroxicam, known modulators of colon tumorigenesis, effect transforming growth factor (TGF)-betas and cyclooxygenase (COX) isozymes in the platelets of colon tumor-bearing male F344 rats. TGF-betas and COXs are important in the development of chronic illnesses including colon cancer. Animals harboring preneoplastic colonic lesions were randomly allocated to a low fat diet (5% by weight--low corn oil, LFC) and three high fat diets (23% by weight--high corn oil, HFC; high corn oil containing 150-ppm piroxicam, HFC+P; and high fish oil, HFF) for 16 weeks. TGF-beta1, TGF-beta2, COX-1 and COX-2 protein levels were assessed in the platelets by Western blot analysis. Active TGF-beta1 (12.5 kDa) level was significantly lower in the platelets of the HFC+P group (p < 0.001), whereas precursor TGF-beta1 (39 kDa) level was significantly lower in the platelets of the HFF group (p < 0.001). The anti-rabbit TGF-beta2 polyclonal antibody did not detect the 13-kDa active TGF-beta2 protein in the platelets. However a 29-kDa protein, potentially a precursor of TGF-beta2, was detected in the platelets of all the groups and was significantly lower in the HFC+P and HFF groups than in LFC and HFC (p < 0.001). COX-1 level was significantly lower in the HFF group than the other three groups (p < 0.001). COX-2 protein was detected in the platelets of all diet groups. Piroxicam in the presence of high corn oil (HFC+P) significantly lowered the level of COX-2 (p < 0.001), without having any effect on COX-1 level. These findings conclusively show that LFC and HFC differ from HFF and HFC+P, and piroxicam differs from fish oil, in regulating the levels of TGF-betas and COX in the platelets. This supports the conjecture that the levels of bioactive constituents of the platelets are profoundly modulated by dietary lipids, which in turn could influence the pathogenesis of chronic illnesses.
 ...
PMID:Differential modulation of transforming growth factor-betas and cyclooxygenases in the platelet lysates of male F344 rats by dietary lipids and piroxicam. 1195 55


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>