• Asian Pacific Journal of Cancer Prevention
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• v.17 no.3
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• pp.1023-1035
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• 2016

The purpose of this study was to investigate the role of colon cancer stem cells (CSCs) during chemically-induced rat multi-step colon carcinogenesis with or without the treatment with a specific cyclooxygenase-2 inhibitor drug (celecoxib). Two experiments were performed, the first, a short term 12 week colon carcinogenesis bioassay in which only surrogate markers for colon cancer, aberrant crypt foci (ACF) lesions, were formed. The other experiment was a medium term colon cancer rat assay in which tumors had developed after 32 weeks. Treatment with celecoxib lowered the numbers of ACF, as well as the tumor volumes and multiplicities after 32 weeks. Immunohistochemical proliferating cell nuclear antigen (PCNA) labeling indexes LI (%) were downregulated after treatment by celecoxib. Also different cell surface antigens known to associate with CSCs such as the epithelial cell adhesion molecule (EpCAM), CD44 and CD133 were compared between the two experiments and showed differential expression patterns depending on the stage of carcinogenesis and treatment with celecoxib. Flow cytometric analysis demonstrated that the numbers of CD133 cells were increased in the colonic epithelium after 12 weeks while those of CD44 but not CD133 cells were increased after 32 weeks. Moreover, aldehyde dehydrogenase-1 activity levels in the colonic epithelium (a known CSC marker) detected by ELISA assay were found down-regulated after 12 weeks, but were up-regulated after 32 weeks. The data have also shown that the protective effect of celecoxib on these specific markers and populations of CSCs and on other molecular processes such as apoptosis targeted by this drug may vary depending on the genetic and phenotypic stages of carcinogenesis. Therefore, uncovering these distinction roles of CSCs during different phases of carcinogenesis and during specific treatment could be useful for targeted therapy.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.9
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• pp.4393-4402
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• 2012

Colon cancer is the third most common malignant neoplasm in the world and it remains an important cause of death, especially in western countries. The toxic environmental pollutant, 1, 2-dimethylhydrazine (DMH), is also a colon-specific carcinogen. Tannic acid (TA) is reported to be effective against various types of chemically induced toxicity and also carcinogenesis. In the present study, we evaluated the chemopreventive efficacy of TA against DMH induced colon toxicity in a rat model. Efficacy of TA against the colon toxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, lipid peroxidation, histopathological changes and expression of early molecular markers of inflammation and tumor promotion. DMH treatment induced oxidative stress enzymes (p<0.001) and an early inflammatory and tumor promotion response in the colons of Wistar rats. TA treatment prevented deteriorative effects induced by DMH through a protective mechanism that involved reduction of oxidative stress as well as COX-2, i-NOS, PCNA protein expression levels and TNF-${\alpha}$ (p<0.001) release. It could be concluded from our results that TA markedly protects against chemically induced colon toxicity and acts plausibly by virtue of its antioxidant, anti-inflammatory and antiproliferative activities.

• Biomedical Science Letters
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• v.19 no.3
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• pp.224-232
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• 2013

Cucurbitacins are a natural cell-permeable triterpenoid compound isolated from Cucurbitaceae and Cruciferae. Cucurbitacins have been used as folk medicine because of their anti-inflammatory and analgesic effects. In the present study, we investigate the anti-cancer effects of cucurbitacin I on colitis-associated colon carcinogenesis induced by azoxymethane (AOM)/dextran sodium sulfate (DSS) in BALB/c mice. Cucurbitacin I treatment attenuated loss of body weight and decreased the number of colon tumors. Western blot analysis showed that cucurbitacin I treatment significantly inhibited the protein expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-${\alpha}$ and interleukin (IL)-6. These results suggest that cucurbitacin I suppressed inflammatory reaction and tumor development in colitis-associated colon carcinogenesis.

• Nutrition Research and Practice
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• v.11 no.4
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• pp.281-289
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• 2017

BACKGROUND/OBJECTIVE: The incidence of colorectal cancer (CRC) has been attributed to higher intake of fat and protein. However, reports on the relationship between protein intake and CRC are inconsistent, possibly due to the complexity of diet composition. In this study, we addressed a question whether alteration of protein intake is independently associated with colonic inflammation and colon carcinogenesis. MATERIALS/METHODS: Balb/c mice were randomly divided into 4 experimental groups: 20% protein (control, 20P, 20% casein/kg diet), 10% protein (10P, 10% casein/kg diet), 30% protein (30P, 30% casein/kg diet), and 50% protein (50P, 50% casein/kg diet) diet groups and were subjected to azoxymethane-dextran sodium sulfate induced colon carcinogenesis. RESULTS: As the protein content of the diet increased, clinical signs of colitis including loss of body weight, rectal bleeding, change in stool consistency, and shortening of the colon were worsened. This was associated with a significant decrease in the survival rate of the mice, an increase in proinflammatory protein expression in the colon, and an increase in mucosal cell proliferation. Further, colon tumor multiplicity was dramatically increased in the 30P (318%) and 50P (438%) groups compared with the control (20P) group. CONCLUSIONS: These results suggest that a high protein diet stimulates colon tumor formation by increasing colonic inflammation and proliferation.

• Intestinal research
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• v.15 no.1
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• pp.75-82
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• 2017

Background/Aims: Cyclooxygenase-2 (COX-2), 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and microsomal prostaglandin E synthase-1 (mPGEs-1) regulate prostaglandin $E_2$ ($PGE_2$) expression and are involved in colon carcinogenesis. We investigated the expression of $PGE_2$ and its regulating genes in sporadic human colon tumors and matched normal tissues. Methods: Twenty colonic adenomas and 27 colonic adenocarcinomas were evaluated. COX-2 and 15-PGDH expression was quantified by real-time polymerase chain reaction. The expression of $PGE_2$ and mPGEs-1 was measured using enzyme-linked immunosorbent assay and Western blotting, respectively. Results: The expression of COX-2, mPGEs-1, and $PGE_2$ did not differ between the adenomas and matched distant normal tissues. 15-PGDH expression was lower in adenomas than in the matched normal colonic tissues (P<0.001). In adenocarcinomas, mPGEs-1 and $PGE_2$ expression was significantly higher (P<0.001 and P=0.020, respectively), and COX-2 expression did not differ from that in normal tissues (P=0.207). 15-PGDH expression was significantly lower in the normal colonic mucosa from adenocarcinoma patients than in the normal mucosa from adenoma patients (P=0.018). Conclusions: Early inactivation of 15-PGDH, followed by activation of COX-2 and mPGEs-1, contributes to $PGE_2$ production, leading to colon carcinogenesis. 15-PGDH might be a novel candidate marker for early detection of field defects in colon carcinogenesis.

• Journal of Ginseng Research
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• v.39 no.1
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• pp.14-21
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• 2015

Background: Colorectal cancer is a leading cause of cancer-related death, and inflammatory bowel disease is a risk factor for this malignancy. We previously reported colon cancer chemoprevention potential using American ginseng (AG) in a xenograft mice model. However, the nude mouse model is not a gut-specific colon carcinogenesis animal model. Methods: In this study, an experimental colitis and colitis-associated colorectal carcinogenesis mouse model, chemically induced by azoxymethane/dextran sodium sulfate (DSS) was established and the effects of oral AG were evaluated. The contents of representative ginseng saponins in the extract were determined. Results: AG significantly reduced experimental colitis measured by the disease activity index scores. This suppression of the experimental colitis was not only evident during DSS treatment, but also very obvious after the cessation of DSS, suggesting that the ginseng significantly promoted recovery from the colitis. Consistent with the anti-inflammation data, we showed that ginseng very significantly attenuated azoxymethane/DSS-induced colon carcinogenesis by reducing the colon tumor number and tumor load. The ginseng also effectively suppressed DSS-induced proinflammatory cytokines activation using an enzyme-linked immunosorbent assay array, in which 12 proinflammatory cytokine levels were assessed, and this effect was supported subsequently by real-time polymerase chain reaction data. Conclusion: AG, as a candidate of botanical-based colon cancer chemoprevention, should be further investigated for its potential clinical utility.

• Proceedings of the Korean Society of Toxicology Conference
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• 2002.05a
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• pp.74-74
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• 2002

Ethyl 3-(4'-geranyloxy-3-methoxyphenyl)-2-propenoate (EGMP) and ferulic acid (FA) have been shown to inhibit development of aberrant crypt foci (ACF) in the azoxymethane (AOM)-treated rat colon. In the present study, inhibitory effects of EGMP and FA on the post-initiation stage of AOM-induced colon carcinogenesis were studied in male ddY mice.(omitted)

• Journal of Veterinary Science
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• v.23 no.5
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• pp.74.1-74.16
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• 2022

Background: Previous studies have presented evidence to support the significant association between red meat intake and colon cancer, suggesting that heme iron plays a key role in colon carcinogenesis. Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, exhibits anti-oxidative and anti-cancer effects. However, the effect of EGCG on red meat-associated colon carcinogenesis is not well understood. Objectives: We aimed to investigate the regulatory effects of hemin and EGCG on colon carcinogenesis and the underlying mechanism of action. Methods: Hemin and EGCG were treated in Caco2 cells to perform the water-soluble tetrazolium salt-1 assay, lactate dehydrogenase release assay, reactive oxygen species (ROS) detection assay, real-time quantitative polymerase chain reaction and western blot. We investigated the regulatory effects of hemin and EGCG on an azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced colon carcinogenesis mouse model. Results: In Caco2 cells, hemin increased cell proliferation and the expression of cell cycle regulatory proteins, and ROS levels. EGCG suppressed hemin-induced cell proliferation and cell cycle regulatory protein expression as well as mitochondrial ROS accumulation. Hemin increased nuclear factor erythroid-2-related factor 2 (Nrf2) expression, but decreased Keap1 expression. EGCG enhanced hemin-induced Nrf2 and antioxidant gene expression. Nrf2 inhibitor reversed EGCG reduced cell proliferation and cell cycle regulatory protein expression. In AOM/DSS mice, hemin treatment induced hyperplastic changes in colon tissues, inhibited by EGCG supplementation. EGCG reduced the hemin-induced numbers of total aberrant crypts and malondialdehyde concentration in the AOM/DSS model. Conclusions: We demonstrated that EGCG reduced hemin-induced proliferation and colon carcinogenesis through Nrf2-inhibited mitochondrial ROS accumulation.

• Proceedings of the Ginseng society Conference
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• 2002.10a
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• pp.277-287
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• 2002

The chemopreventive effects of ginseng on rat carcinogenesis models were investigated, In the present study, the inhibitory effects of white and red ginseng on tumor development were examined using medium-term liver, initiation and medium-term multi-organ carcinogenicity bioassay systems. No modifying potential of the ginsengs was evident in terms of the numbers or areas of glutathione S-transferase placental form (GST -P)-positive foci, which is a marker of preneoplastic lesion in rat livers. However, white ginseng, but not red ginseng was found to decrease the incidences of adenocarcinoma of the small intestine and colon in the medium-term multi-organ carcinogenesis model. These results indicate that white ginseng may have inhibitory effects on progression stage of rat intestinal carcinogenesis, but the influence is not strong. Ginseng is unlikely to have promoting or inhibitory effects in other organs under the present type of experimental conditions. Possible application on ginseng for chemoprevention of colon cancer in humans, can be concluded given the lack of obvious adverse effects.

• Nutritional Sciences
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• v.4 no.2
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• pp.73-78
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• 2001

This study investigated the effect of different dietary fats and fibers on colon tumor incidence and cell proliferation, the levels of eicosanoids and polyamines in colonic mucosa of DMH-treated rats. The experiment was conducted on male Sprague Dawley rats using a 2 $\times$3 factorial design with two fats (corn oil and DHA-rich fish oil) and two fibers (cellulose and pectin) and a fiber-free control. The rats were find an experimental diet containing 15% (w/w) dietary fat and 6% (w/w) fiber for 25 weeks. Tumor incidence was Bower in rats fed fish oil as opposed to corn oil. The levels of arachidonic acid (AA) and eicosanoids ($PGE_2, and TXB_2$) in normal colonic mucosa were significantly lower in rats fed fish oil and there was a concomitant increase of docosahexaenoic acid (DHA). The levels of eicosanoids and AA in tumor tissues were significantly higher than those of normal colonic mucosa. The level of polyamines in normal colonic mucosa was not affected by dietary fats but was significantly lower than that in rumor tissues. Dietary fiber did not have a significant effect on rumor incidence and the levels of AA, eicosanoids and polyamines. Overall, fish oil rich in DHA reduced cell prolifiration and thus inhibited colon carcinogenesis through its effect on the distribution of AA and production of eicosanoids in normal colonic mucosa. However, its effect on colon carcinogenesis revealed a lack of consistency depending on the type of dietary fiber in diet.