The NSAID sulindac is chemopreventive in the mouse distal colon but carcinogenic in the proximal colon

Mladenova, Dessislava; Daniel, Joseph J.; Dahlstrom, Jane E.; Bean, Elaine; Gupta, Ruta; Pickford, Russell; Currey, Nicola; Musgrove, Elizabeth A.; Kohonen‐Corish, Maija

doi:10.1136/gut.2010.208314

Cited by 31 publications

(64 citation statements)

References 46 publications

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“…This is consistent with clinical practice, where colon and rectal cancers are treated as distinct entities (47), and a growing body of evidence that associations between dietary patterns, chemoprotective nonsteroidal anti-inflammatory drugs (NSAIDs), and CRC risk differ across anatomic subsites (21,37). In contrast, a recent comprehensive molecular characterization of human colon and rectal cancer demonstrated that after excluding hypermutated cancers, colon and rectal cancers appear to have similar patterns of genomic alteration (40).…”

mentioning

confidence: 73%

Comprehensive site-specific whole genome profiling of stromal and epithelial colonic gene signatures in human sigmoid colon and rectal tissue

Knight

Kim

Ivanov

et al. 2016

Physiological Genomics

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mentioning

confidence: 73%

Comprehensive site-specific whole genome profiling of stromal and epithelial colonic gene signatures in human sigmoid colon and rectal tissue

Knight

Kim

Ivanov

et al. 2016

Physiological Genomics

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“…Recently, it is reported that the effect of a nonsteroidal anti-inflammatory agent sulindac inhibited tumorigenesis in the distal colon in a murine model. However, it augmented carcinogenesis in the proximal colon in mismatch repair-deficient mice, suggesting that depending on the oncogenic changes, differential responses are noted in the colon [35].…”

Section: Discussionmentioning

confidence: 98%

Differential expression of TNF-α signaling molecules and ERK1 in distal and proximal colonic tumors associated with obesity

2011

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Distal and proximal colon cancers have been recognized as two different disease types in human population. The environmental factors involved in the pathogenesis of the proximal and distal tumors also differ. The main objective of this study was to determine if obesity-augmented colonic tumors differ from each other if they are located in different regions of the colonic axis. Zucker obese rats were injected with azoxymethane (AOM) 10 mg/kg body weight/week for 2 weeks. The tumors appeared within 20 weeks. The highest proportion of the tumors was in the distal colon, and the number declined towards the splenic flexure. A number of proteins previously reported to be altered in tumor tissue were assessed in the present study in tumors appearing in proximal and distal regions. Distal colonic tumors had higher TNF-α R2, NF-κB, and IκBα levels than tumors of proximal origin. In contrast, IKKβ was decreased in the proximal tumors. Insulin receptor and insulin-like growth factor-1R were higher in distal tumors. The mitogen-activated protein kinase (ERK2) levels were similar in the tumor groups; however, the ERK1 was significantly higher in the distal tumor than in the proximal tumor. Our findings suggest that colon tumors induced by AOM in different colonic regions are different from each other with respect to differential expression of proteins and support the concept that these disease states could respond differently to tumor-promoting and inhibitory conditions. Moreover, these findings support the concept that cancer preventive or therapeutic agents need to be evaluated for their effectiveness on proximal as well as on distal tumors.

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“…Since disease susceptibility of the colon exhibits an anatomical bias with respect to dietary risk factors and chemoprevention (Mladenova et al, 2011; Hjartaker et al, 2013; Parr et al, 2013), the effect of nutritional combinations on intestinal biology is typically assessed in both the proximal and distal colon. Due to the low level of apoptosis in non-carcinogen treated mice, the apoptotic index is expressed as the total number of apoptotic cells per 100 crypts as previously reported (Davidson et al, 2012), instead of per crypt column.…”

Section: Discussionmentioning

confidence: 99%

Dietary fat and fiber interactively modulate apoptosis and mitochondrial bioenergetic profiles in mouse colon in a site-specific manner

Yang

Vaz

Chapkin

2017

European Journal of Cancer Prevention

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We have demonstrated that the combination of bioactive components generated by fish oil (containing n-3 polyunsaturated fatty acids) and fermentable fiber (leading to butyrate production) act coordinately to protect against colon cancer. This is the result, in part, to an enhancement of apoptosis at the base of the crypt throughout all stages (initiation, promotion and progression) of colon tumorigenesis. Since mitochondria are key organelles capable of regulating the intrinsic apoptotic pathway and mediating programmed cell death, we investigated the effects of diet on mitochondrial function by measuring mucosal cardiolipin composition, mitochondrial respiratory parameters and apoptosis in isolated crypts from the proximal and distal colon. C57BL/6 mice (n=15 per treatment) were fed one of two dietary fats (corn oil and fish oil) and two fibers (pectin and cellulose) for 4 wk in a 2 × 2 factorial design. In general, diet modulated apoptosis and the mucosal bioenergetic profiles in a site-specific manner. The fish/pectin diet promoted a more proapoptotic phenotype, e.g., increased proton leak (P-interaction = 0.002), compared to corn/cellulose (control) only in the proximal colon. With respect to the composition of cardiolipin, a unique phospholipid localized to the mitochondrial inner membrane where it mediates energy metabolism, fish oil feeding indirectly influenced its molecular species with a combined carbon number of C68 or greater, suggesting compensatory regulation. These data indicate that dietary fat and fiber can interactively modulate the mitochondrial metabolic profile and thereby potentially modulate apoptosis and subsequent colon cancer risk.

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The NSAID sulindac is chemopreventive in the mouse distal colon but carcinogenic in the proximal colon

Cited by 31 publications

References 46 publications

Comprehensive site-specific whole genome profiling of stromal and epithelial colonic gene signatures in human sigmoid colon and rectal tissue

Comprehensive site-specific whole genome profiling of stromal and epithelial colonic gene signatures in human sigmoid colon and rectal tissue

Differential expression of TNF-α signaling molecules and ERK1 in distal and proximal colonic tumors associated with obesity

Dietary fat and fiber interactively modulate apoptosis and mitochondrial bioenergetic profiles in mouse colon in a site-specific manner

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