Effect of Concomitant Polyethylene Glycol and Celecoxib on Colonic Aberrant Crypt Foci and Tumors in F344 Rats

Do, Khoa; Barnard, Graham F.

doi:10.1007/s10620-005-2777-4

Cited by 3 publications

(3 citation statements)

References 24 publications

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“…is mediated, at least partly, by suppression of epithelial proliferation (16,19). PEG markedly reduced BrdUrd incorporation in both the ACF and the uninvolved mucosa.…”

Section: Discussionmentioning

confidence: 99%

Chemoprevention of colon carcinogenesis by polyethylene glycol: suppression of epithelial proliferation via modulation of SNAIL/β-catenin signaling

Roy

Kunte

Koetsier

et al. 2006

Molecular Cancer Therapeutics

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Polyethylene glycol (PEG) is one of the most potent chemopreventive agents against colorectal cancer; however, the mechanisms remain largely unexplored. In this study, we assessed the ability of PEG to target cyclin D1 -B-catenin -mediated hyperproliferation in the azoxymethane-treated rat model and the human colorectal cancer cell line, HT-29. Azoxymethane-treated rats were randomized to AIN-76A diet alone or supplemented with 5% PEG-8000. After 30 weeks, animals were euthanized and biopsies of aberrant crypt foci and uninvolved crypts were subjected to immunohistochemical and immunoblot analyses. PEG markedly suppressed both early and late markers of azoxymethane-induced colon carcinogenesis (fractal dimension by 80%, aberrant crypt foci by 64%, and tumors by 74%). In both azoxymethane-treated rats and HT-29 cells treated with 5% PEG-3350 for 24 hours, PEG decreased proliferation (45% and 52%, respectively) and cyclin D1 (78% and 56%, respectively). Because B-catenin is the major regulator of cyclin D1 in colorectal cancer, we used the T-cell factor (Tcf) -TOPFLASH reporter assay to show that PEG markedly inhibited B-catenin transcriptional activity. PEG did not alter total B-catenin expression but rather its nuclear localization, leading us to assess E-cadherin expression (a major determinant of B-catenin subcellular localization), which was increased by 73% and 71% in the azoxymethane-rat and HT-29 cells, respectively. We therefore investigated the effect of PEG treatment on levels of the negative regulator of E-cadherin, SNAIL, and observed a 50% and 75% decrease, respectively. In conclusion, we show, for the first time, a molecular mechanism through which PEG imparts its antiproliferative and hence profound chemopreventive effect.

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“…is mediated, at least partly, by suppression of epithelial proliferation (16,19). PEG markedly reduced BrdUrd incorporation in both the ACF and the uninvolved mucosa.…”

Section: Discussionmentioning

confidence: 99%

Chemoprevention of colon carcinogenesis by polyethylene glycol: suppression of epithelial proliferation via modulation of SNAIL/β-catenin signaling

Roy

Kunte

Koetsier

et al. 2006

Molecular Cancer Therapeutics

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“…Several mechanisms have been proposed to explain its pathophysiology, such as chronic inflammation, recurrent infections 3 , pH changes, nitrosamine production by bacteria, and genetic instability of the anastomotic areas 4 , among other cases, but there are many variables that have not been uncovered. Various authors have reported the inhibitory effect of celecoxib on ACF 6 . The inhibition and reduction of COX-2, NFkβ and interleukins in rats and the protection of bone marrow cells subjected to chemical carcinogenesis in different organs have been observed by various authors 7,8 .…”

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confidence: 99%

Carcinogenesis in rats subjected to a new model ureterosigmoidostomy and treated with L-lysine

Santos¹,

Coelho

Azevedo

et al. 2016

Acta Cir. Bras.

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PURPOSE:To evaluate the effects of L-lysine on the intestinal and urothelial epithelium of rats subjected to ureterosigmoidostomy (new model for surgical carcinogenesis). METHODS:Forty-two rats, 9 weeks of age, were divided into 6 groups. Animals in groups A, B, C were subjected to ureterosigmoidostomy (US) and treated with L-lysine, celecoxib and H 2 O, respectively. Groups D, E and F (non-operated controls) received L-lysine, celecoxib and H 2 O, respectively. The L-lysine dose was 150 mg/kg and that of celecoxib was 20 mg/kg. The colon was analyzed for the presence of aberrant crypt foci (ACF) under a stereomicroscope.The tissue was stained with hematoxylin and eosin and PAS alcian blue. RESULTS:There were rare ACF, and there was no statistically significant difference between the groups. Histopathologic study of the ureteral epithelium identified moderate to severe urothelial hyperplasia in rats with ureterosigmoidostomy. Transitional hyperplasia in the ureters of animals receiving L-lysine (A) showed an apparent difference compared to the control (C) (P=0.2424). There was no dysplasia or atypia.CONCLUSION: L-lysine does not promote carcinogenesis of the intestinal and urethelial epithelium of rats subjected to ureterosigmoidostomy at the doses and times studied.

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“…Finally, increased colonic proliferation has been considered an early biomarker of increased colon cancer susceptibility (23). Previous studies reported decreased tumor development during PEG treatment in different mouse and rat models of colon cancer (8,12,32). A population-based study in patients undergoing colonoscopy showed a lower prevalence of colorectal tumors in PEG4000 users (13).…”

Section: Discussionmentioning

confidence: 87%

Laxative treatment with polyethylene glycol decreases microbial primary bile salt dehydroxylation and lipid metabolism in the intestine of rats

Wulp

Derrien

Stellaard

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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van der Wulp MY, Derrien M, Stellaard F, Wolters H, Kleerebezem M, Dekker J, Rings EH, Groen AK, Verkade HJ. Laxative treatment with polyethylene glycol decreases microbial primary bile salt dehydroxylation and lipid metabolism in the intestine of rats. Am J Physiol Gastrointest Liver Physiol 305: G474 -G482, 2013. First published July 18, 2013; doi:10.1152/ajpgi.00375.2012.-Polyethylene glycol (PEG) is a frequently used osmotic laxative that accelerates gastrointestinal transit. It has remained unclear, however, whether PEG affects intestinal functions. We aimed to determine the effect of PEG treatment on intestinal sterol metabolism. Rats were treated with PEG in drinking water (7%) for 2 wk or left untreated (controls). We studied the enterohepatic circulation of the major bile salt (BS) cholate with a plasma stable isotope dilution technique and determined BS profiles and concentrations in bile, intestinal lumen contents, and feces. We determined the fecal excretion of cholesterol plus its intestinally formed metabolites. Finally, we determined the cytolytic activity of fecal water (a surrogate marker of colorectal cancer risk) and the amount and composition of fecal microbiota. Compared with control rats, PEG treatment increased the pool size (ϩ51%; P Ͻ 0.01) and decreased the fractional turnover of cholate (Ϫ32%; P Ͻ 0.01). PEG did not affect the cholate synthesis rate, corresponding with an unaffected fecal primary BS excretion. PEG reduced fecal excretion of secondary BS and of cholesterol metabolites (each P Ͻ 0.01). PEG decreased the cytolytic activity of fecal water [54 (46 -62) vs. 87 (85-92)% erythrocyte potassium release in PEG-treated and control rats, respectively; P Ͻ 0.01]. PEG treatment increased the contribution of Verrucomicrobia (P Ͻ 0.01) and decreased that of Firmicutes (P Ͻ 0.01) in fecal flora. We concluded that PEG treatment changes the intestinal bacterial composition, decreases the bacterial dehydroxylation of primary BS and the metabolism of cholesterol, and increases the pool size of the primary BS cholate in rats.cholate; enterohepatic circulation; bile salt; microbiota POLYETHYLENE GLYCOL (PEG) presently is one of the most widely prescribed laxatives. Long-term treatment with PEG is believed to be safe and highly effective (11,27). However, it is not known whether or not long-term PEG treatment affects specific intestinal metabolic functions. PEG may change the intestinal milieu by accelerating the passage of luminal contents and/or by increasing the luminal water content, possibly leading to a change in the intestinal microflora (10).We have previously shown that PEG treatment accelerates the transit through the small intestine as well as the whole gut in rats (10). PEG decreases fecal excretion of bile salts (BS) in rats (10). BS facilitate the solubilization of lipids (dietary fats, cholesterol, and fat-soluble vitamins) in the small intestine, which is required for efficient lipid absorption (41). It has recently become clear that BS not only are detergents necessary for lip...

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Effect of Concomitant Polyethylene Glycol and Celecoxib on Colonic Aberrant Crypt Foci and Tumors in F344 Rats

Cited by 3 publications

References 24 publications

Chemoprevention of colon carcinogenesis by polyethylene glycol: suppression of epithelial proliferation via modulation of SNAIL/β-catenin signaling

Chemoprevention of colon carcinogenesis by polyethylene glycol: suppression of epithelial proliferation via modulation of SNAIL/β-catenin signaling

Carcinogenesis in rats subjected to a new model ureterosigmoidostomy and treated with L-lysine

Laxative treatment with polyethylene glycol decreases microbial primary bile salt dehydroxylation and lipid metabolism in the intestine of rats

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