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)

Since ethacrynic acid (EA), an SH modifier as well as glutathione S-transferase (GST) inhibitor, has been suggested to induce apoptosis in some cell lines, its effects on a human colon cancer cell line DLD-1 were examined. EA enhanced cell proliferation at 20-40 microM, while it caused cell death at 60-100 microM. Caspase inhibitors did not block cell death and DNA ladder formation was not detected. Poly(ADP-ribose) polymerase, however, was cleaved into an 82-kDa fragment, different from an 85-kDa fragment that is specific for apoptosisis. The 82-kDa fragment was not recognized by antibody against PARP fragment cleaved by caspase 3. N-Acetyl-L-cysteine (NAC) completely inhibited EA-induced cell death, but 3(2)-t-butyl-4-hydroxyanisole or pyrrolidinedithiocarbamate ammonium salt did not. Glutathione (GSH) levels were dose-dependently increased in cells treated with EA and this increase was hardly affected by NAC addition. Mitogen-activated protein kinase (MAPK) kinase (MEK) 1, extracellular signal-regulated kinase (ERK) 1 and GST P1-1 were increased in cells treated with 25-75 microM EA, while c-Jun N-terminal kinase (JNK) 1 and p38 MAPK were markedly decreased by 100 microM EA. NAC repressed EA-induced alterations in these MAPKs and GST P1-1. p38 MAPK inhibitors, SB203580 and FR167653, dose-dependently enhanced EA-induced cell death. An MEK inhibitor, U0126, did not affect EA-induced cell death. These studies revealed that EA induced cell death concomitantly with a novel PARP fragmentation, but without DNA fragmentation. p38 MAPK was suggested to play an inhibitory role in EA-induced cell death.
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PMID:Characterization of cell death induced by ethacrynic acid in a human colon cancer cell line DLD-1 and suppression by N-acetyl-L-cysteine. 1455 62

In this study, we show that the novel synthetic curcumin analog, EF24, induces cell cycle arrest and apoptosis by means of a redox-dependent mechanism in MDA-MB-231 human breast cancer cells and DU-145 human prostate cancer cells. Cell cycle analysis demonstrated that EF24 causes a G2/M arrest in both cell lines, and that this cell cycle arrest is followed by the induction of apoptosis as evidenced by caspase-3 activation, phosphatidylserine externalization and an increased number of cells with a sub-G1 DNA fraction. In addition, we demonstrate that EF24 induces a depolarization of the mitochondrial membrane potential, suggesting that the compound may also induce apoptosis by altering mitochondrial function. EF24, like curcumin, serves as a Michael acceptor reacting with glutathione (GSH) and thioredoxin 1. Reaction of EF24 with these agents in vivo significantly reduced intracellular GSH as well as oxidized GSH in both the wild-type and Bcl-xL overexpressing HT29 human colon cancer cells. We therefore propose that the anticancer effect of a novel curcumin analog, EF24, is mediated in part by redox-mediated induction of apoptosis.
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PMID:EF24, a novel synthetic curcumin analog, induces apoptosis in cancer cells via a redox-dependent mechanism. 1571 Nov 78

Oxidative stress is a characteristic of cancerous colon tissue and inflammatory bowel diseases that increase colon cancer risk. Epidemiological evidence supports a protective effect of plant-derived compounds. Aspirin is also protective against colon cancer. The mechanism of action is unclear although salicylic acid, the main metabolite of aspirin, has been shown to decrease the synthesis of pro-inflammatory and potentially neo-plastic prostaglandins. Salicylic acid is found in significant quantities in a plant-based diet. However, in plants salicylic acid is also reported to modulate the expression of numerous enzymes with antioxidant activity. The aim of this study was to assess whether salicylic acid can modulate pro-cancerous biological pathways in the colon. Oxidative stress, prostaglandins and cytosolic glutathione peroxidase (cyGPX) were analysed in proximal, transverse and distal colon from a rat model of diet-induced oxidative stress. Elevated plasma pyruvate kinase activity (1293+/-206 U/ml) and increased indices of lipid peroxidation in colon (proximal 6.4+/-0.84 nM MDA/mg protein; transverse 6.9+/-0.97 nM MDA/mg protein; distal 5.2+/-0.62 nM MDA/mg protein) from rats fed a Vitamin E deficient diet were significantly decreased on supplementation with salicylic acid (plasma pyruvate 546+/-43 U/ml; salicylic acid proximal 3.6+/-0.39 nM MDA/mg protein; transverse 4.5+/-0.61 nM MDA/mg protein; distal 4.4+/-0.27 nM MDA/mg protein). Reductions in oxidative stress and prostaglandin production on supplementation with salicylic acid were associated with an elevation in glutathione peroxidase activity (Vitamin E deficient proximal 0.056+/-0.013 U/mg protein; transverse 0.073+/-0.008 U/mg protein; distal 0.088+/-0.010 U/mg protein; Vitamin E deficient with salicylic acid proximal 0.17+/-0.01 U/mg protein; transverse 0.23+/-0.016 U/mg protein; distal 0.16+/-0.020 U/mg protein). Gpx1 and Gpx2 gene transcripts were not elevated in association with increased activity of the soluble glutathione peroxidase activity. Glutathione peroxidases are key antioxidant enzymes, catalysing the decomposition of potentially toxic lipid peroxides. Gpx activity and regulation of Gpx gene transcription has been shown previously to be complex with activity not necessarily mirrored by a corresponding elevation in gene transcription. By supplementing the diet of Vitamin E deficient rats with salicylic acid (1 g/kg diet), this study assessed effects of salicylic acid on cytosolic glutathione peroxidase activity in the colon. The ability of salicylic acid to modulate antioxidant enzymes in colon tissue may be an important mechanism in inhibiting colon cancer development.
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PMID:Salicylic acid modulates oxidative stress and glutathione peroxidase activity in the rat colon. 1603 82

Glutathione peroxidases (Gpx) are important moderators of oxidative stress that is implicated in the pathogenesis of numerous diseases including colon cancer. Previous studies report limited examinations of cytosolic glutathione peroxidase location of expression in colon tissue. This study reports evidence of both common sites of Gpx1 and Gpx2 expression in rat colon and sites that are exclusive to each isoform. Semi-quantitative PCR performed previously demonstrated RNA expression of Gpx1 and Gpx2 in proximal, transverse and distal colon. Mapping the distribution throughout the entire colon has revealed specific, novel sites of glutathione peroxidase expression in colon lymphatic tissue. In situ hybridisation and immunohistochemistry confirmed micro-anatomical location of Gpx1 within lymphatic tissue and the lamina propria, sub-mucosa, muscularis and serosa, but not the lumenal epithelium. In situ hybridisation and immunohistochemistry were consistent with reports of microanatomical location of Gpx2 in the lumenal epithelium. Novel sites of Gpx2 expression were also observed in lymphatic tissue. Immunolocalisation in the vicinity of aberrant crypt foci was also examined to further investigate the link between glutathione peroxidases and colon cancer. This did not reveal significant abnormalities, nor did measurement of cytosolic glutathione peroxidase activity or gene expression in colon tissue from rats treated with the colontropic chemical, 1,2-dimethylhydrazine. These results support the potential for Gpx1 and Gpx2 redundancy in lymphatic tissue, but not in epithelial cells of the colon crypt or in the lamina propria, sub-mucosa, muscularis or serosa.
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PMID:Novel sites of cytosolic glutathione peroxidase expression in colon. 1622 41

2-Nitrosoamino-3,8-dimethylimidazo[4,5-f]quinoxaline (N-NO-MeIQx) is a nitrosation product of the food carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and is proposed to form in vivo under inflammatory conditions. This study evaluated the stability and reactivity of N-NO-MeIQx to assess its possible role in the initiation of colon cancer by MeIQx. 14C-N-NO-MeIQx (4 microM) was incubated for 4 h over a range of pH values, and its stability was monitored by HPLC. At pH values from pH 7.4 to 9.0, N-NO-MeIQx was very stable with no detectable change observed. Glutathione (1 mM) did not alter stability at pH 7.4. As the pH decreased, this nitrosamine was less stable with only 48 +/- 1% remaining at pH 5.5 and none remaining at pH 3.5 or 2.0. Major products identified by electrospray ionization mass spectrometry were 3,8-dimethylimidazo[4,5-f]quinoxaline and 2-hydroxy-3,8-dimethylimidazo[4,5-f]quinoxaline. MeIQx was a minor product. At pH 2.0, the t(1/2) for N-NO-MeIQx was reduced from 2.1 +/- 0.2 to 1.2 +/- 0.1 min with 10 mM NaN3. This effect of azide was due to the formation of 2-azido-MeIQx. The binding of 14C-N-NO-MeIQx to DNA increased with decreasing pH. The 10-fold increase in binding observed at pH 2.0 as compared to pH 5.5 was completely inhibited by 10 mM NaN3 due to 2-azido-MeIQx formation. The reactivity of N-NO-MeIQx was compared to N-OH-MeIQx by evaluating adduct formation with 2'-deoxyguanosine 3'-monophosphate (dGp) by 32P-postlabeling. N-OH-MeIQx formed a single major adduct, N-(deoxyguanosin-8-yl)-MeIQx (dG-C8-MeIQx). Incubation of N-NO-MeIQx under inflammatory conditions (pH 5.5 +/- HOCl) produced dG-C8-MeIQx along with 4-6 other adducts. dG-C8-MeIQx formation increased in the presence of HOCl. Liver from a MeIQx-treated mouse contained dG-C8-MeIQx and two other adducts detected with N-NO-MeIQx but not N-OH-MeIQx. These results suggest that N-NO-MeIQx could be genotoxic, is activated by conditions that mediate inflammatory responses, and is a possible cancer risk factor for individuals with inflammation of the colon.
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PMID:Stability and reactivity of 2-nitrosoamino-3,8-dimethylimidazo[4,5-f]quinoxaline. 1648 10

The folate antagonist methotrexate (MTX) inhibits synthesis of tetrahydrofolate (THF), pyrimidines and purines, and induces differentiation in several cell types. At 1 microM, MTX reduced proliferation and induced differentiation in HT29 colon cancer cells; the latter effect was augmented (P < 0.001) by thymidine (100 microM) but was reversed (P < 0.001) by the purines, hypoxanthine (Hx; 100 microM) and adenosine (100 microM). In contrast 5-fluoro-uracil (5-FU), a specific thymidylate synthase (TS) inhibitor, had no effect on differentiation, suggesting that MTX-induced differentiation is not due to a reduction in thymidine but to the inhibition of purine biosynthesis. Inhibition of cyclic AMP (cAMP) by RpcAMP (25 microM) further enhanced (P < 0.001) MTX induced differentiation, whereas the cAMP activator forskolin (10 microM) reversed (P < 0.001) MTX induced differentiation. These observations implicate a central role of adenosine and cAMP in MTX induced differentiation. By combining Western blot analysis with liquid chromatography-mass spectrometry (LC-MS)and HPLC analyses we also reveal both the expression and activity of key enzymes (i.e. methionine synthase (MS), s-adenosylhomocysteinase, cystathionine beta-synthase and ornithine decarboxylase) regulating methyl cycle, transsulfuration and polyamine pathways in HT29 colon cancer cells. At 1 microM, MTX induced differentiation was associated with a marked reduction in the intracellular concentrations of adenosine and, consequently, S-adenosylmethionine (SAM), S-adenosylhomocysteine, polyamines and glutathione (GSH). Importantly, the marked reduction in methionine that accompanied MS inhibition following MTX treatment was non-limiting with respect to SAM synthesis. Collectively, these findings indicate that the effects of MTX on cellular differentiation and single carbon metabolism are primarily due to the intracellular depletion of purines.
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PMID:Methotrexate induced differentiation in colon cancer cells is primarily due to purine deprivation. 1659 58

The role of obesity in diabetes mellitus, hyperlipidemia, colon cancer, sudden death and other cardiovascular diseases has confirmed in many recent research studies. In present study, it is hypothesized that obesity can serve as an independent risk factor for the decreased activities of cytoprotective antioxidants in humans and for the associated systemic oxidative stress. 150 age matched, female subjects with no history of smoking or biochemical evidence of diabetes mellitus, hypertension, hyperlipidemia, renal or liver disease or cancer were included in the study and were divided into different grades of obesity according to their body mass index (BMI). Hemoglobin and erythrocyte glutathione (GSH) concentrations were measured for each subject. The study suggests that increase BMI was found to be associated with a significant decrease in erythrocyte glutathione concentration. From these observations it is concluded that obesity even in the absence of smoking, diabetes mellitus, hyperlipidemia, renal or liver diseases can decrease the activities of body's protective antioxidants, and can enhance the systemic oxidative stress and should therefore receive the same attention as obesity with complications.
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PMID:Obesity: an independent risk factor for systemic oxidative stress. 1663 56

Preclinical studies have suggested that the long-term use of antidepressants may result in the initiation and/or promotion of tumor in the gastrointestinal tract. However, a possible relationship between the use of antidepressants and the production of colon cancer has not yet been confirmed, and hence requires to be further investigated. To address this issue, the effects of antidepressants on the proliferation of colorectal tumor cells were examined using human HT29 colon carcinoma cells, and tricyclic antidepressant, such as imipramine, desipramine and amitriptyline, were shown to reduce the cell viability in a manner dependent on the time exposing to these drugs. In addition to these drugs, a selective serotonin reuptake inhibitor fluoxetine, but not a monoamine oxidase inhibitor tranylcypromine, caused the reduction of cell viability, similar in extent to that caused by imipramine. Further studies showed that desipramine caused the apoptotic cell death, which could be prevented by neither catalase, reduced-form glutathione (GSH), nor N-acetylcysteine (NAC), without accompanying the disruption of mitochondrial membrane potential within the cells and the release of cytochrome c into the cell cytoplasm. Moreover, desipramine caused the arrest of cell-cycle progression at either G0/G1-phase or G2/M-phase, which might be depending upon the drug concentration. Thus, these results suggest that tricyclic antidepressants may be cytotoxic, and induce the non-oxidative apoptotic death of human HT29 colon carcinoma cells probably through a non-mitochondrial pathway associated with the cell-cycle progression.
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PMID:Characterization of cytotoxic actions of tricyclic antidepressants on human HT29 colon carcinoma cells. 1675 42

Gastric cancer and colon cancer are major causes of mortality and morbidity worldwide. Many cancers manifest due to changes in gene expression, particularly those involved in cellular proliferation and apoptosis. Apoptosis is an important process that removes damaged or deleterious cells and contributes to normal cellular and tissue homeostasis. Apoptosis is a tightly regulated process mediated by caspases, and the involvement of the Bcl-2 superfamily of membrane bound proteins, among others. Thus, the therapeutic induction of apoptosis has been proposed as a novel method to eliminate cancer cells. The oxidative pentose pathway (OPP) and the glutathione (GSH) antioxidant defense system play an important role in the regulation of cell growth and apoptosis. The OPP regulates intracellular redox status and provides NADPH for the synthesis of GSH, an important antioxidant. GSH is required to inactivate intracellular reactive oxygen species (ROS) which induce apoptosis and cell injury. Depletion of GSH increases the sensitivity of cells to ROS. Many chemotherapeutic agents induce apoptosis through ROS-mediated cell damage. Therefore, we speculate that the therapeutic inhibition of the OPP and/or the GSH defense system may increase the sensitivity of gastric and colon cancer cells to anti-cancer therapy. Moreover, we hypothesize that the short-chain fatty acid, butyrate, will induce apoptosis in gastric cancer cells and, secondly, that differences in butyrate metabolism will exist between these cancer cell lines.
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PMID:Nutrient and antioxidant modulation of apoptosis in gastric and colon cancer cells. 1676 Jun 45

Colon cancer is a leading cause of cancer death and its prevention is of great interest throughout the world. This study was conducted to examine the efficacy of different doses of dietary caraway (Carum carvi L.) on tissue lipid peroxidation (LPO) and antioxidant profile in rat colon carcinogenesis. Wistar male rats were divided into 6 groups and were fed a modified pellet diet for the whole of 30 weeks. To induce colon cancer, rats were given a weekly subcutaneous injection of 1,2-dimethylhydrazine (DMH) at a dose of 20 mg kg(-1) (based on body weight) for the first 15 weeks. Caraway was supplemented every day orally at doses of 30, 60 and 90 mg kg(-1) for different groups of rats for the total period of 30 weeks. All rats were sacrificed at the end of 30 weeks, the colons were examined visually for masses and were subsequently evaluated histologically. The results showed diminished levels of intestinal, colonic and caecal LPO products, such as conjugated dienes (CD), lipid hydroperoxides (LOOH) and thiobarbituric acid reactive substances (TBARS) and also the antioxidants superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathione reductase (GR) in DMH treated rats, which were significantly reversed (P<0.05) on caraway supplementation. Moreover, enhanced activity of intestinal, colonic and caecal glutathione peroxidase (GPx), glutathione S-transferase (GST) and colonic ascorbic acid and alpha-tocopherol levels were observed in carcinogen-treated rats, which were significantly (P<0.05) reduced on caraway supplementation. Thus, our study showed that caraway supplementation at a dose of 60 mg kg(-1) had a modulatory role on tissue LPO, antioxidant profile and prevented DMH-induced histopathological lesions in colon cancer rats.
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PMID:Dose-response efficacy of caraway (Carum carvi L.) on tissue lipid peroxidation and antioxidant profile in rat colon carcinogenesis. 1687 60


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