Barbara Simi

Effect of dietary fiber on colonic bacterial enzymes and bile acids in relation to colon cancer

Because of the potential significance of colonic bacteria and secondary bile acids in the pathogenesis of colon cancer, the present study investigated the effect of different types of dietary fiber on fecal bacterial enzymes, namely, beta-glucuronidase, 7 alpha-dehydroxylase, nitroreductase, and azoreductase, and on bile acids and neutral sterols in premenopausal women. The subjects consumed 13-15 g of wheat, oat, or corn bran daily for 8 weeks in addition to their normal diet. Stools collected during the normal and fiber diet periods were analyzed for the above constituents. Dietary wheat bran decreased the concentrations of fecal deoxycholic acid, lithocholic acid, 12-ketolithocholic acid, and neutral sterols and the activities of all bacterial enzymes. Oat bran had no effect on secondary bile acids and 7 alpha-dehydroxylase but decreased beta-glucuronidase, nitroreductase, and azoreductase levels. Dietary corn bran increased 7 alpha-dehydroxylase, lithocholic acid, and cholesterol levels and decreased deoxycholic acid coprostanol, cholestenone, nitroreductase, and azoreductase levels. These results show that the modifying effect of dietary fiber on secondary bile acids and bacterial enzymes that may play a role in carcinogenesis depends on the type of fiber consumed.

Pterostilbene, an Active Constituent of Blueberries, Suppresses Aberrant Crypt Foci Formation in the Azoxymethane-Induced Colon Carcinogenesis Model in Rats

Purpose: Epidemiologic studies have linked the consumption of fruits and vegetables to reduced risk of several types of cancer. Laboratory animal model studies have provided evidence that stilbenes, phenolic compounds present in grapes and blueberries, play a role in inhibiting the risk of certain cancers. Pterostilbene, a naturally occurring stilbene from blueberries, was tested for its preventive activity against colon carcinogenesis. Experimental Design: Experiments were designed to study the inhibitory effect of pterostilbene against the formation of azoxymethane-induced colonic aberrant crypt foci (ACF) preneoplastic lesions in male F344 rats. Beginning at 7 weeks of age, rats were treated with azoxymethane (15 mg/kg body weight s.c., once weekly for 2 weeks). One day after the second azoxymethane treatment, rats were fed experimental diets containing 0 or 40 ppm of pterostilbene. At 8 weeks after the second azoxymethane treatment, all rats were sacrificed, and colons were evaluated for ACF formation and for inhibition of inducible nitric oxide synthase (iNOS) and proliferating cell nuclear antigen. Effects on mucin MUC2 were also determined. Results: Administration of pterostilbene for 8 weeks significantly suppressed azoxymethane-induced formation of ACF (57% inhibition, P < 0.001) and multiple clusters of aberrant crypts (29% inhibition, P < 0.01). Importantly, dietary pterostilbene also suppressed azoxymethane-induced colonic cell proliferation and iNOS expression. Inhibition of iNOS expression by pterostilbene was confirmed in cultured human colon cancer cells. Conclusions: The results of the present study suggest that pterostilbene, a compound present in blueberries, is of great interest for the prevention of colon cancer.

Prevention of Colon Cancer by Low Doses of Celecoxib, a Cyclooxygenase Inhibitor, Administered in Diet Rich in ω-3 Polyunsaturated Fatty Acids

Epidemiologic and animal studies suggest that a high-fat diet containing mixed lipids promotes colorectal cancer, whereas fish oil lacks promoting effect. Although cyclooxygenase-2 (COX-2) inhibitors are effective chemopreventive agents against colon carcinogenesis, administration of high doses of these agents over time may induce side effects. Here, we compared the efficacy of moderately high and low doses of celecoxib administered in diets high in mixed lipids (HFML) or fish oil (HFFO) against azoxymethane-induced colon carcinogenesis in male F344 rats. One day after the last azoxymethane treatment (15 mg/kg body weight once weekly for 2 weeks), groups of rats were fed the HFML and HFFO diets containing 0, 250, 500, and 1,000 ppm celecoxib. Rats were killed 26 weeks later and colon tumors were subjected to histopathologic examination and analyzed for total COX and COX-2 synthetic activities and COX-2 expression. Rats fed the HFFO diet showed significantly lower colon tumor incidence and multiplicity compared with rats fed the HFML diet. Celecoxib at 250, 500, and 1,000 ppm in either diet significantly suppressed colon carcinogenesis. Inhibition of colon adenocarcinomas were more pronounced in animals given 250 ppm celecoxib in HFFO diet compared with 250 ppm celecoxib given in HFML diet, suggesting some synergism between omega-3 polyunsaturated fatty acids (PUFA) and celecoxib. Inhibition of colon tumors by celecoxib was associated with lower levels of COX-2 activity and expression in colon tumors. These studies support the use of low doses of celecoxib in omega-3 PUFA-rich diet as a promising approach for clinical trials.

Combination of atorvastatin with sulindac or naproxen profoundly inhibits colonic adenocarcinomas by suppressing the p65/β-catenin/cyclin D1 signaling pathway in rats.

Evidence supports the protective role of nonsteroidal anti-inflammatory drugs (NSAID) and statins against colon cancer. Experiments were designed to evaluate the efficacies atorvastatin and NSAIDs administered individually and in combination against colon tumor formation. F344 rats were fed AIN-76A diet, and colon tumors were induced with azoxymethane. One week after the second azoxymethane treatment, groups of rats were fed diets containing atorvastatin (200 ppm), sulindac (100 ppm), naproxen (150 ppm), or their combinations with low-dose atorvastatin (100 ppm) for 45 weeks. Administration of atorvastatin at 200 ppm significantly suppressed both adenocarcinoma incidence (52% reduction, P = 0.005) and multiplicity (58% reduction, P = 0.008). Most importantly, colon tumor multiplicities were profoundly decreased (80%–85% reduction, P < 0.0001) when given low-dose atorvastatin with either sulindac or naproxen. Also, a significant inhibition of colon tumor incidence was observed when given a low-dose atorvastatin with either sulindac (P = 0.001) or naproxen (P = 0.0005). Proliferation markers, proliferating cell nuclear antigen, cyclin D1, and β-catenin in tumors of rats exposed to sulindac, naproxen, atorvastatin, and/or combinations showed a significant suppression. Importantly, colon adenocarcinomas from atorvastatin and NSAIDs fed animals showed reduced key inflammatory markers, inducible nitric oxide synthase and COX-2, phospho-p65, as well as inflammatory cytokines, TNF-α, interleukin (IL)-1β, and IL-4. Overall, this is the first report on the combination treatment using low-dose atorvastatin with either low-dose sulindac or naproxen, which greatly suppress the colon adenocarcinoma incidence and multiplicity. Our results suggest that low-dose atorvastatin with sulindac or naproxen might potentially be useful combinations for colon cancer prevention in humans. Cancer Prev Res; 4(11); 1895–902. ©2011 AACR.

Biochemical epidemiology of colon cancer: Effect of types of dietary fiber on colonic diacylglycerols in women

BACKGROUND/AIMS In view of the potential significance of dietary fat and fiber in colon cancer and the possible indirect involvement of diacylglycerols (DAGs) in the pathogenesis of colon cancer, the effect of types of dietary fiber on fecal DAG in premenopausal women was investigated. METHODS Forty-eight women consuming a typical western diet provided two 24-hour stool specimens and two sets of preintervention 4-day food records. They were randomly assigned to one of the fiber groups, namely, a wheat, oat, or corn bran supplement. They consumed their control diet plus 13-15 g of dietary fiber from each source for 8 weeks. At the end of the fiber period, each subject provided two 24-hour stool specimens and 4-day food records. Stool samples collected during the two periods were analyzed for total fat and DAG fatty acids. RESULTS All sources of dietary fiber increased the amount of fecal fat excreted. Dietary wheat bran decreased the concentrations of total DAG and DAG containing lauric acid, myristic acid, palmitic acid, stearic acid, and linoleic acid, whereas oat bran increased the DAG composed of oleic acid and linoleic acid compared with the control diet. Corn bran decreased the DAG containing stearic acid. CONCLUSIONS These results show that the modifying effect of dietary fiber on DAG depends on the type of fiber consumed.

Effects of Combination of Calcium and Aspirin on Azoxymethane-Induced Aberrant Crypt Foci Formation in the Colons of Mice and Rats

Human intervention studies have suggested an exciting synergistic action between calcium supplementation and aspirin intake in reducing the risk of colorectal cancer. The aim of this study was to determine whether such a synergy can be demonstrated on azoxymethane (AOM)-induced colon aberrant crypt foci (ACF) formation in mice and rats. Female CF-1 mice and male F344 rats were injected subcutaneously with AOM and then received diet treatments for 8 wk. The basal control diet contained high fat (20% mixed lipids by weight) and low calcium (1.4 mg/g diet) to mimic the average Western diet. The treatment diets contained enriched calcium (5.2 mg calcium/g diet), aspirin (0.2 mg aspirin/g diet), or calcium plus aspirin (5.2 mg calcium plus 0.2 mg aspirin/g diet). Treatment with calcium, aspirin, or their combination significantly decreased the number of total ACF and aberrant crypt per mouse (by 43–59%) or rat (by 23–38%), but statistically significant differences among the 3 groups were not observed. A hint of additivity between calcium and aspirin was observed in mice but not in rats. These results indicate that the combination of calcium and aspirin did not produce a synergistic effect on the ACF formation in AOM-treated mice and rats.

Abstract 833: Combination of atorvastatin with sulindac or naproxen profoundly inhibits colonic adenocarcinomas by suppressing the p65/beta-catenin/cyclin D1 signaling pathway in rats

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Colorectal cancer is the third leading cause of death from cancer worldwide. Evidence support the protective role of non-steroidal anti-inflammatory drugs (NSAIDs) and statins. Experiments were designed to evaluate the efficacies atorvastatin and NSAIDs administered individually and in combination against colon adenocarcinoma (AdCa) formation. Also, we evaluated colonic AdCa inhibitory action of atorvastatin and NSAIDs in regulating the expression of key protein markers and cytokines. F344 rats were fed AIN-76A diet and colon AdCa were induced with azoxymethane (AOM). One week after AOM-treatment (adenoma-stage) groups of rats were fed AIN-76A diet containing atorvastatin (200 ppm), sulindac (100 ppm) or naproxen (150 ppm), or their combinations with atorvastatin (100 ppm) for 45 weeks. We found that rats fed experimental diets were comparable body weights and without any observable toxicity. Most of AOM-treated control-diet fed rats developed AdCa (74.2% incidence) at 45 weeks. Administration of sulindac and naproxen individually had modest inhibitory (∼25% incidence and ∼33% multiplicity) effect on colon AdCa. However, 200 ppm atorvastatin significantly suppressed both AdCa incidence (>52%, p<0.005) and multiplicity (59%, p<0.003). Importantly, colon AdCa incidence was significantly decreased when rats were given low-dose atorvastatin with either sulindac (p<0.001) or naproxen (p <0.0005). Also, colon AdCa multiplicities were profoundly reduced (80-85%, p<0.0001) when rats were given low-dose atorvastatin with either sulindac or naproxen. The staining of proliferation markers, PCNA, cyclin D1 and beta-catenin indicated that the tumors from the control group had the strong positive staining in the cells, whereas sulindac, naproxen, atorvastatin, and/or combinations had much weaker positive staining. Importantly, colon AdCa from atorvastatin and NSAIDs fed animals showed reduced expression of key inflammatory markers as well as nuclear staining for phospho-p65, a key molecule in the NF-kB pathway. In addition, atorvastatin and NSAIDs combination decreased mucosal and colonic tumor levels of the pro-inflammatory cytokines, TNF- alpha, IL-1 beta, IL-4 and IL-10. Overall, this is the first report on the combination treatment using low-dose atorvastatin with either low dose sulindac or naproxen, which greatly suppress the colon AdCa incidence and multiplicity. Also, our results suggest that decreased inflammatory cytokines and signaling molecules, particularly inhibition of nuclear p65, beta-catenin and cyclin D1 are responsible for suppression of colonic AdCa. In summary, low-dose atorvastatin with sulindac or naproxen might potential useful combinations for colon cancer prevention in humans. (Supported by NCI-N01-CN-53300 and R01-CA94962) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 833. doi:10.1158/1538-7445.AM2011-833