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)

Previously we reported that auraptene was a potent suppressant for matrix metalloproteinase (MMP)-7 expression in HT-29 human colon cancer cells. In the present study, we examined the effects of auraptene on MMP-2, -7, and -9 expression in colonic mucosa from dextran sulfate sodium (DSS)-induced ulcerative colitis mice. Auraptene remarkably suppressed the DSS-induced gelatinolytic activity of MMP-7 as well as the expression of MMP-2 and -9, suggesting that it might be useful in anti-metastatic therapies via the targeting of MMPs.
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PMID:Auraptene decreases the activity of matrix metalloproteinases in dextran sulfate sodium-induced ulcerative colitis in ICR mice. 1715 46

Bioassay-guided fractionation of the active BuOH extract of the sea cucumber Pseudocolochirus violaceus resulted in the isolation of three new sulfated triterpene glycosides, i.e., violaceusides I, II, and III (1-3, resp.), as active compounds causing morphological abnormality of Pyricularia oryzae mycelia. Their structures were elucidated by spectroscopic methods including 2D-NMR and MS experiments, as well as chemical evidence. Compounds 1-3 exhibit the same structural features, i.e., the presence of a 16-oxo group in the holostane-type triterpene aglycone with the C(7)=C(8) bond, but differ in the side chains and the tetrasaccharide moieties. Compound 1 possesses one sulfate group, while 2 and 3 are disulfated glycosides. All the glycosides showed significant in vitro cytotoxicities against human gastric cancer MKN-45 and human colon cancer HCT-116 cells.
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PMID:Cytotoxic sulfated triterpene glycosides from the sea cucumber Pseudocolochirus violaceus. 1719 13

The incidence of colon cancer increases with age, and this may be related to altered metabolism and disposition of carcinogens. One such carcinogen implicated in colon cancer is the heterocyclic amine found in well done meat, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). The purpose of these studies was to determine whether the disposition and metabolism of IQ changes with age, comparing young (3-month) and old (22- to 24-month) male F344 rats. Animals were treated with vehicle or beta-naphthoflavone (BNF), an inducer of drug-metabolizing cytochromes P450. Disposition and metabolism of IQ were determined after i.p. injection of radiolabeled IQ. Urinary IQ metabolites were identified and quantitated by high-performance liquid chromatography and mass spectroscopy. In BNF-treated animals, total radiolabeled IQ excretion by old rats was less than half that of young rats. Binding of radiolabeled IQ metabolites by the old kidney was 10 times higher than that of the young. There were no age differences in intestinal and hepatic binding. There was a significant age-related increase in IQ conjugation to glucuronic acid and a decrease in conjugation to sulfate regardless of treatment. The induction of renal CYP1A1, a major P450 involved in IQ metabolism, by BNF did not change with age. Changes in IQ metabolism with age along with altered renal function may contribute to the decreased urinary excretion and increased renal binding of IQ and/or its metabolites seen in the old animals.
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PMID:Metabolism of a heterocyclic amine colon carcinogen in young and old rats. 1725 6

Intestinal injury or chronic inflammation induce cytokines that promote crypt regeneration and mucosal repair. If excessive or prolonged, such mechanisms may increase colon cancer risk. Factors that terminate or limit cytokine action in intestinal epithelial cells (IEC) may protect against crypt hyperplasia and neoplasia. We hypothesized that suppressor of cytokine signaling-3 (SOCS3) is such a factor. Mice with Vilin-promoter/Cre-recombinase (VC)-mediated IEC-specific SOCS3 gene disruption (VC/HO), WT/HO littermates with floxed but intact SOCS3 genes and VC/WT mice were studied. Colon was examined after acute dextran sodium sulfate (DSS)-induced mucosal injury or after azoxymethane (AOM) and chronic DSS. Signaling pathways were examined in colon, cultured IEC or colon cancer cell lines. VC/HO mice showed no basal phenotype. After acute DSS, VC/HO exhibited enhanced crypt proliferation and crypt hyperplasia and reduced transforming growth factor (TGF) beta expression in colon. Inflammation and mucosal damage were similar across genotypes. Following AOM/DSS, VC/HO mice had increased size, number and load of colonic tumors and increased STAT3 and nuclear factor-kappa B (NF-kappaB) activation in colon. In vitro, SOCS3 overexpression reduced proliferation, IL-6-mediated STAT3 activation and tumor necrosis factor (TNF) alpha-mediated NF-kappaB activation. We conclude that cytokine induction of SOCS3 normally provides an intrinsic mechanism to limit injury-induced crypt hyperproliferation and inflammation-associated colon cancer by regulating both STAT3 and NF-kappaB pathways.
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PMID:Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon. 1729 44

The present study describes a novel bacterial isolate exhibiting high ability to synthesise and secrete butyrate. The novel isolated bacterium was obtained from human faeces and grown in selective liquid intestinal microflora medium containing rumen fluid under microaerobic conditions. Its probiotic properties were demonstrated by the ability of the isolate to survive high acidity and medium containing bile acids and the ability to adhere to colon cancer cells (Caco-2) in vitro. Phylogenetic identity to Enterococcus durans was established using specific primers for 16S rRNA (99% probability). PCR analyses with primers to the bacterial gene encoding butyrate kinase, present in the butyrogenic bacteria Clostridium, showed that this gene is present in E. durans. The in vivo immunoprotective and anti-inflammatory effects of E. durans were assessed in dextran sodium sulfate (DSS)-induced colitis in Balb/c mice. Administration of E. durans ameliorated histological, clinical and biochemical scores directly related to intestinal inflammation whereas the lactic acid bacterium Lactobacillus delbrueckii was ineffective in this regard. Colonic cDNA concentrations of IL-1beta and TNF-alpha were significantly down regulated in DSS-treated E. durans-fed mice but not in control or DSS-treated L. delbrueckii- fed mice. Fluorescent in situ hybridisation analyses of colonic tissue from mice fed E. durans, using a butyrate kinase probe, demonstrated that E. durans significantly adheres to the colonic tissue. The novel isolated bacterium described in the present paper, upon further characterisation, can be developed into a useful probiotic aimed at the treatment of patients suffering from ulcerative colitis.
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PMID:Isolation and characterisation of new putative probiotic bacteria from human colonic flora. 1734 85

It is generally assumed that inflammation influences carcinogenesis. We previously reported that dextran sodium sulfate (DSS) strongly enhances colon carcinogenesis in the Apc(Min/+) mice and the over-expression of inducible nitric oxide synthase (iNOS) contributes to this enhancement. In the current study, we investigated the effect of a selective iNOS inhibitor, ONO-1714 on colitis-related colon carcinogenesis in the Apc(Min/+) mouse treated with DSS. Male C57BL/6J Apc(Min/+) and Apc(+/+) mice were exposed to 1% DSS in their drinking water for 7 days. ONO-1714 was given to the mice at a dose level of 50 or 100 ppm in diet for 5 weeks (during the administration of DSS). The tumor inhibitory effects by ONO-1714 were assessed at week 5 by counting the incidence and multiplicity of colonic neoplasms. Additionally, we assessed serum lipid levels and colonic mRNA expression for cyclooxygenase (COX)-2, iNOS, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. Feeding with ONO-1714 significantly inhibited the occurrence of colonic adenocarcinoma in a dose-dependent manner in the Apc(Min/+) mice. In addition, the treatment with ONO-1714 significantly lowered the serum triglyceride levels and mRNA expression levels of COX-2, TNFalpha and IL-1beta of colonic mucosa in the DSS-treated Apc(Min/+) mice. Neither ONO-1714 nor DSS affected the colonic pathology in the Apc(+/+) mice. Our findings may suggest that ONO-1714 could therefore serve as an effective agent for suppression of colitis-related colon cancer development in the Apc(Min/+) mice.
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PMID:A specific inducible nitric oxide synthase inhibitor, ONO-1714 attenuates inflammation-related large bowel carcinogenesis in male Apc(Min/+) mice. 1741 80

The prognosis of peritoneal spread from gastrointestinal cancer and subsequent malignant ascites is poor, and current medical treatments available are mostly ineffective. Targeted chemotherapy with intraperitoneal prodrug activation may be a beneficial new approach. L293 cells were genetically modified to express the cytochrome P450 enzyme 2B1 under the control of a cytomegalovirus immediate early promoter. This CYP2B 1 enzyme converts ifosfamide to its active cytotoxic compounds. The cells are encapsulated in a cellulose sulfate formulation (Capcell; Bavarian Nordic, Martinsried, Germany). Adult Balb/c mice were inoculated intraperitoneally (i.p.) with 1 x 10(6) colon cancer cells, previously transfected with GFP to emit a stable green fluorescence, by injection into the left lower abdominal quadrant. Two or five day's later animals were randomly subjected to either i.p. treatment with ifosfamide alone or ifosfamide combined with microencapsulated CYP2B1 expressing cells. Peritoneal tumour volume and tumour viability were assessed 10 days after tumour inoculation by means of fluorescence microscopy, spectroscopy and histology. Early i.p. treatment with ifosfamide and CYP2B1 cells resulted in a complete response. Treatment starting on day five and single-drug treatment with ifosfamide resulted in a partial response. These results suggest that targeted i.p. chemotherapy using a combination of a prodrug and its converting enzyme may be a successful treatment strategy for peritoneal spread from colorectal cancer. In summary, by using GFP-transfected colon 26 tumour cells in mice we established a well reproducible animal model of metastatic peritoneal cancer. Fluorescent imaging of GFP-transfected tumour was used to demonstrate tumour distribution in the peritoneal cavity and to estimate tumour growth and tumour response to treatment in this model. The application of Capcell and ifosfamide into the peritoneal cavity is a safe and well tolerated procedure in animal models and may help to target chemotherapeutic agents specifically at metastatic peritoneal cancer.
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PMID:Targeted intraabdominal chemotherapy for peritoneal carcinomatosis. 1763 75

Dietary calcium (Ca) positively modulates the susceptibility to colon cancer, but its effects on related or earlier colonic pathologies, such as inflammation and mucosal dysregulation, are poorly understood. We tested the effects of differing dietary Ca levels on acute dextran sulfate sodium (DSS)-induced colitis in mice. BALB/c mice received a normal Ca (NCa) diet (0.5% Ca), a high Ca (HCa) diet (1.5% Ca), a low Ca (LCa) diet (0.05% Ca), or a very low Ca (VLCa) diet (0.009% Ca) for 3 wk. Mucosal caspases 1, 3, and 9 were assessed by Western blotting, and the histological crypt score was assessed by microscopy. Half of the mice in each group received DSS (1.5%) for 20 d in their drinking water, and disease activity was assessed. Increasing or lowering dietary Ca increased mucosal caspases (P < 0.0001 vs. NCa). Crypt scores increased with decreasing dietary Ca levels (P < 0.0001, r = -0.675), indicating that elevated caspases in LCa groups reflected early subclinical inflammation. DSS-induced disease activity was higher in mice fed low dietary Ca levels [P < 0.0001, VLCa and DSS vs. NCa and DSS (NCaDSS) and P < 0.005, LCa and DSS vs. NCaDSS], and mice from the VLCa group were moribund within 11 d of DSS administration. Those in the HCa group did not differ greatly from controls. Together, these data indicate that Ca protects against DSS-induced colitis in mice. The mechanisms are unclear, but the calcium-sensing receptor and/or luminal precipitates of calcium phosphate microparticles may be involved. Whether these observations can be extended to patients with colitis or infectious diarrhea deserves consideration.
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PMID:Low dietary calcium levels modulate mucosal caspase expression and increase disease activity in mice with dextran sulfate sodium induced colitis. 1795 88

The inflammatory bowel disease ulcerative colitis (UC) frequently progresses to colon cancer. To understand the mechanisms by which UC patients develop colon carcinomas, we used a mouse model of the disease whereby administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion causes severe colonic inflammation and the subsequent development of multiple tumors. We found that treating WT mice with AOM and DSS increased TNF-alpha expression and the number of infiltrating leukocytes expressing its major receptor, p55 (TNF-Rp55), in the lamina propria and submucosal regions of the colon. This was followed by the development of multiple colonic tumors. Mice lacking TNF-Rp55 and treated with AOM and DSS showed reduced mucosal damage, reduced infiltration of macrophages and neutrophils, and attenuated subsequent tumor formation. WT mice transplanted with TNF-Rp55-deficient bone marrow also developed significantly fewer tumors after AOM and DSS treatment than either WT mice or TNF-Rp55-deficient mice transplanted with WT bone marrow. Furthermore, administration of etanercept, a specific antagonist of TNF-alpha, to WT mice after treatment with AOM and DSS markedly reduced the number and size of tumors and reduced colonic infiltration by neutrophils and macrophages. These observations identify TNF-alpha as a crucial mediator of the initiation and progression of colitis-associated colon carcinogenesis and suggest that targeting TNF-alpha may be useful in treating colon cancer in individuals with UC.
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PMID:Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. 1821 90

Previously, we have shown that DA-6034, a synthetic derivative of flavonoid eupatilin, inhibited NF-kappaB activation in colon epithelial cells and prevented trinitrobenzene sulfonic acid-induced rat colitis. The aim of this study was to investigate the preventive and therapeutic effect of DA-6034 on dextran sulfate sodium (DSS)-induced colitis and on inflammation-related cancer. C57BL/6 mice were given 4% DSS for 5 days with and without DA-6034 in the acute preventive model. In the acute therapeutic model, mice were given 4% DSS for 5 days followed by rectal administration of DA-6034. Colitis was quantified by body weight, disease activity index (DAI), colon length, and histology. In the inflammation-related cancer model, mice were given a single intraperitoneal injection of azoxymethane, then three cycles of 2% DSS for 5 days, then 2 weeks of free water consumption. Apoptosis was determined by in situ terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay, and the expression of Ki-67, phospho-kappaB kinase alpha (IKKalpha), and COX-2 were evaluated by immunohistochemistry. In both the acute preventive and acute therapeutic models, DA-6034 significantly attenuated DSS-induced weight loss, an increase in DAI, and a shortening of colon length. DA-6034-treated mice maintained crypt architecture and revealed a scanty infiltration of inflammatory cells in both the preventive and therapeutic models. In the inflammation-related cancer model, DA-6034 reduced the number of colon tumors and ameliorated weight loss and shortening of colon length. DA-6034 strongly enhanced apoptosis and inhibited the expression of COX-2 and phospho-IKKalpha in inflammation-related colon cancer models. Our results suggest that DA-6034 prevents acute murine colitis and inhibits inflammation-related colon carcinogenesis. DA-6034 could be a potential therapeutic agent for inflammatory bowel disease.
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PMID:DA-6034, a derivative of flavonoid, prevents and ameliorates dextran sulfate sodium-induced colitis and inhibits colon carcinogenesis. 1822 73


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