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)

Epidemiological, experimental and clinical results suggest that aspirin and other NSAIDs (non-steroidal anti-inflammatory drugs) inhibit the development of colon cancer. It has been shown that the NSAID sulindac induces apoptosis and suppresses carcinogenesis, in part, by a mechanism leading to the transcriptional activation of the gene encoding SSAT (spermidine/spermine N1-acetyltransferase), a rate-limiting enzyme in polyamine catabolism. In the present study, we show that a variety of NSAIDs, including aspirin, sulindac, ibuprofen and indomethacin, can induce SSAT gene expression in Caco-2 cells. Aspirin, at physiological concentrations, can induce SSAT mRNA via transcriptional initiation mechanisms. This induction leads to increased SSAT protein levels and enzyme activity. Promoter deletion analysis of the 5' SSAT promoter-flanking region led to the identification of two NF-kappaB (nuclear factor kappaB) response elements. Electrophoretic mobility-shift assays showed binding of NF-kappaB complexes at these sequences after aspirin treatment. Aspirin treatment led to the activation of NF-kappaB signalling and increased binding at these NF-kappaB sites in the SSAT promoter, hence providing a potential mechanism for the induction of SSAT by aspirin in these cells. Aspirin-induced SSAT ultimately leads to a decrease in cellular polyamine content, which has been associated with decreased carcinogenesis. These results suggest that activation of SSAT by aspirin and different NSAIDs may be a common property of NSAIDs that plays an important role in their chemopreventive actions in colorectal cancer.
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PMID:Induction of spermidine/spermine N1-acetyltransferase (SSAT) by aspirin in Caco-2 colon cancer cells. 1626 3

Nitric oxide-donating aspirin (NO-ASA) is a promising chemoprevention agent against colon cancer and other cancers. It consists of traditional ASA to which a NO-releasing moiety is bound through a spacer. NO-ASA inhibits colon cancer cell growth several hundred times more potently than does ASA. In Min mice, NO-ASA inhibited intestinal carcinogenesis without affecting cell proliferation. Thus, we examined whether NO-ASA's most important cell kinetic effect is the induction of apoptosis. After confirming induction of apoptosis in Min mice, we studied the underlying mechanism in human colon adenocarcinoma cells. NO-ASA's spacer formed a conjugate with glutathione, depleting glutathione stores. This induced oxidative stress (increased intracellular levels of peroxides and O(2)(.-)) leads to apoptosis by activating the intrinsic apoptosis pathway. NO-ASA disrupted adherens junctions by inducing cleavage of beta- and gamma-catenin, resulting in cell detachment. NO-ASA inhibited Wnt signaling by a dual mechanism: at low concentrations it blocked the formation of beta-catenin/Tcf complexes (dominant mechanism), and at higher concentrations it also cleaved beta-catenin. These findings provide a mechanism of action by a potent chemopreventive agent, underscore the significance of these pathways in regulating cell death in the context of cancer chemoprevention, and present a paradigm for developing agents with enhanced cancer cell growth inhibitory properties.
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PMID:Nitric oxide-donating aspirin induces apoptosis in human colon cancer cells through induction of oxidative stress. 1628 76

Acetylsalicylic acid (aspirin; 2-acetoxybenzoic acid) has been used for >100 years for pain relief and to treat inflammatory conditions and fevers. More recently, regular intake has been associated with decreased incidence of certain cancers, particularly colon cancer. After absorption aspirin is very rapidly hydrolysed to salicylic acid (2-hydroxybenzoic acid). The anti-cancer effects of aspirin may be a result of salicylic acid reducing the transcription of prostaglandin H(2)-synthase and thereby the synthesis of pro-inflammatory and potentially-neoplastic prostaglandins. Salicylic acid is widely present in plants and functions as a hormonal mediator of the systemic acquired resistance response to pathogen attack and environmental stress. Thus, it is present in a large range of fruit, vegetables, herbs and spices of dietary relevance. Consequently, the recognised effect of consuming fruit and vegetables on lowering risk of colon cancer may be partly attributable to salicylates in plant-based foods. The present review discusses which types of fruit and vegetables are the richest source of salicylates and whether they are sufficiently released from the food matrix to modify the key cellular events associated with the pathogenesis of colon cancer.
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PMID:Is there a role for dietary salicylates in health? 1644 48

Several case control studies have demonstrated that in patients with ulcerative colitis, ingestion of 5-ASA is correlated with a reduced risk of developing colon cancer. A recent editorial in The American Journal of Gastroenterology concluded that "a 5-ASA tablet a day keeps the cancer away". However, the clinical studies in the meta-analysis upon which this conclusion is based are relatively small, and confounding could explain the observed correlation. A large study in which a chemoprotective effect of 5-ASA could not be found has been presented but has not yet been published. It would be advisable to wait for further documentation before 5-ASA is prescribed for chemo prevention of colonic cancer.
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PMID:[Does 5-ASA prevent development of colon cancer in ulcerative colitis?]. 1676 21

Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) inhibit proliferation of human colon cancer cells in vitro. Transmission electron microscope detected morphological features of apoptosis in the aspirin-treated (5 mM, 72 h) HT-29 cells in which cyclooxygenoase-2 is catalytically inactive. We investigated aspirin-induced genome-wide expression changes in HT-29 cells and further studied the time- and concentration-dependent expression changes in 374 apoptosis-related genes, which is the first to show stimulation of genome-wide expression of HT-29 cells by aspirin. The most marked effects of aspirin are on ribosome assembly and rRNA metabolism, which could explain why the quasi-apoptotic morphological changes are not accompanied by a classical DNA ladder. These findings demonstrate that aspirin induces apoptosis in HT-29 cells, bolstering the hypothesis that apoptosis may be a mechanism by which NSAIDs inhibit colon carcinogenesis.
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PMID:Cyclooxygenase-independent effects of aspirin on HT-29 human colon cancer cells, revealed by oligonucleotide microarrays. 1681 85

Obesity is a risk factor for colon cancer, possibly due to elevated levels of circulating cytokines derived from adipose tissue. Aspirin, which may affect the levels of these cytokines, has been shown in randomized controlled trials to decrease the risk of colorectal adenomas. We hypothesized that the chemopreventive effect of aspirin might be greater in individuals with higher body mass index (BMI). Data were available from the Aspirin/Folate Polyp Prevention Study, a randomized controlled trial of aspirin and folic acid to prevent recurrent colorectal adenomas. Obesity was defined as BMI > or = 30 (kg/m2), overweight as BMI of 25-29 (kg/m2) and normal weight as BMI <25 (kg/m2). For the analysis of the effect of aspirin on the recurrence of colorectal adenoma by BMI, we computed risk ratios for aspirin versus placebo within the three BMI strata using a modified Poisson model. Overall the risk reduction of adenomas with a daily dose of 325 mg aspirin was greater among subjects with higher BMI. Among obese subjects the risk ratio (RR) for advanced adenomas compared with placebo was 0.44 (95% CI 0.17-1.10), versus RR = 1.23 (95% CI 0.55-2.77) among those with normal weight. However, 81 mg aspirin daily did not interact with BMI to modify the risk of adenomas in such a fashion. The more pronounced effect of 325 mg aspirin in individuals with higher BMI suggests a possible protective role of anti-inflammatory aspirin against increased adipose-driven cytokines among obese subjects.
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PMID:Aspirin may be more effective in preventing colorectal adenomas in patients with higher BMI (United States). 1711 Dec 62

Several plant-based nutrients and non-nutrients that can inhibit mutagenesis and proliferation have been identified. Some of the most promising nutrients identified as chemopreventive agents in colon cancer prevention include isoflavones, curcumin, calcium, vitamin D and more recently Green tea polyphenols (GTP). In addition to inhibiting mutagenesis and proliferation, these compounds are relatively non-toxic, are of low cost and can be taken orally or as a part of the daily diet. Epidemiological and laboratory studies have identified epigallocatechin gallate (EGCG) in green tea polyphenols (GTP), as the most potent chemopreventive agent that can induce apoptosis, suppress the formation and growth of human cancers including colorectal cancers (CRC). It is only logical then, that future clinical studies should focus on examining the efficacy of phytochemicals such as EGCG in cancer chemoprevention as an alternative to pharmacological agents, especially in populations where administration of COX-2 inhibitors, Aspirin and NSAIDS is contraindicated. The goal of this review is to provide the rationale, and discuss the use of EGCG in GTP as a chemopreventive agent for prevention of colon carcinogenesis and present evidence for the efficacy and safety of these agents based on epidemiological, animal, in vitro studies and Phase I clinical trials.
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PMID:Green tea polyphenols in the prevention of colon cancer. 1712 41

Aspirin and other nonsteroidal anti-inflammatory drugs prevent some cases of colon cancer by inhibiting prostaglandin (PG) synthesis. PGE(2) promotes colon neoplasia, as shown by knockout mouse studies on enzymes and receptors in the PG cascade. A few experiments 20 to 30 years ago suggested that PGD(2) may suppress tumors, but a role for biosynthetic enzymes for PGD(2) in tumor development has not been studied. We report here that disruption of the gene for hematopoietic PGD synthase in Apc(Min/+) mice led to approximately 50% more intestinal adenomas compared with controls. Tumor size was not affected. By immunohistochemistry, we detected hematopoietic PGD synthase mainly in macrophages and monocytes of the gut mucosa. The mean number of tumors did not increase with knockout of the gene for the lipocalin type of the enzyme, which is not produced in the intestine. On the other hand, Apc(Min/+) mice with transgenic human hematopoietic PGD synthase tended to have 80% fewer intestinal adenomas. The transgene produced high mRNA levels (375-fold over endogenous). There was a suggestion of higher urinary excretion of 11beta-PGF(2alpha) and a lower excretion of a PGE(2) metabolite in transgenic mice, but differences (30-40%) were not statistically significant. The results support an interpretation that hematopoietic PGD synthase controls an inhibitory effect on intestinal tumors. Further studies will be needed to prove possible mechanisms, such as routing of PG production away from protumorigenic PGE(2) or inhibition of the nuclear factor-kappaB cascade by PGD(2) metabolites.
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PMID:Hematopoietic prostaglandin D synthase suppresses intestinal adenomas in ApcMin/+ mice. 1728 18

Aberrant nuclear factor-kappaB (NF-kappaB) signaling plays a role in cancer initiation and progression; thus, it represents a potential therapeutic target. We previously identified a mechanism of repression of NF-kappaB transcriptional activity and induction of apoptosis in colon cancer cells involving nuclear/nucleolar translocation of the RelA (p65) component of NF-kappaB. This response was stimulated by cellular stress-inducing agents, including aspirin, but not by tumor necrosis factor. Here, we investigate the upstream molecular mechanisms responsible for nucleolar targeting of RelA and show that aspirin activates the p38 mitogen-activated protein kinase (MAPK) pathway in colorectal cancer cells. We also show that aspirin causes rapid, ubiquitin-dependent degradation of cyclin D1, a known p38 target. Aspirin-induced p38 activation preceded cyclin D1 degradation, which was then followed by activation of the NF-kappaB pathway, suggesting a causative link. Indeed, chemical p38 inhibition (PD169316) and small interfering RNA directed against p38 blocked aspirin-induced cyclin D1 degradation, nucleolar translocation of RelA, and apoptosis. Furthermore, chemical inhibition of the cyclin D1/cyclin-dependent kinase 4 (CDK4) kinase complex, used as a surrogate for cyclin D1 degradation, caused nucleolar translocation of RelA, repression of kappaB-driven transcription, and apoptosis, thereby reproducing the effects of aspirin. In addition, we found that aspirin and the CDK4 inhibitor induced nucleolar translocation of RelA and apoptosis through a common mechanism involving the NH(2)-terminal nucleolar localization signal. Collectively, these data suggest that aspirin causes inhibition of cyclin D1/CDK4 through the p38 MAPK pathway. This inhibition stimulates the NF-kappaB pathway to induce nucleolar translocation of RelA and apoptosis. These novel findings have considerable relevance to the rational design of novel chemotherapeutic and chemopreventative strategies.
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PMID:p38-mediated inactivation of cyclin D1/cyclin-dependent kinase 4 stimulates nucleolar translocation of RelA and apoptosis in colorectal cancer cells. 1730 7

NO-donating aspirin (NO-ASA) is a promising anticancer drug. We studied the contribution of NO-ASA's components (ASA, NO-releasing moiety, and spacer linking them) to its effect. The ASA and NO-releasing moieties play no biological role: ASA inhibits the growth of colon cancer cells >100-fold less potently that NO-ASA; and denitrated NO-ASA plus the NO-donor SNAP releasing the same amount of NO as NO-ASA, inhibit the growth of cancer cells >50-fold less potently than NO-ASA. The biologically active moiety of NO-ASA is the spacer: it is chemically reactive (studies with NO-ASA radiolabeled at the spacer demonstrated that it binds to proteins); and compounds in which the ASA or the NO-releasing groups are replaced inhibit cell growth similar to NO-ASA. We propose a mechanism of action of NO-ASA involving formation of quinone methide from its para and ortho isomers and of a carbocation from the meta, with the NO-releasing group functioning as a leaving group.
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PMID:The mechanism of action of nitric oxide-donating aspirin. 1751


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