**2.4.3.1 Vitamins (except vitamin D)**

218 Cancer Prevention – From Mechanisms to Translational Benefits

markers of inflammation in the colonic biopsies or feces, the genotoxicity markers in colonocyte, and apoptotic and mitotic rate in colonic mucosa (Pot et al., 2009; Pot et al.,

An animal study showed that fish oil significantly reduced colon tumors (Rao et al., 2001). A diet including fish oil and pectin protects against colon cancer, compared with that of corn oil and cellulose azoxymethane, which induced colon cancer in model rats (Cho et al., 2011). The preventive mechanisms of fish have been proposed to include the effects on gene expression, decreasing adhesion genes such as *B44galt1* at the initiation stage, lowering the expression of both cell promoters and suppressors at the aberrant crypt foci (ACF) stage, and increasing apoptosis inducing genes at the tumor stage. These modifications may be associated to the induction of apoptosis and the suppression of proliferation (Cho et al., 2011). Fish n-3 polyunsaturated fatty acids (PUFAs) may reduce eicosanoid biosynthesis derived from n-6 PUFA to protect tissue from inflammation, and inhibit COX-2 (Rao et al.,

On the other hand, it has been reported that dietary fish oil containing docosahexaenoic acid (DHA) promotes inflammation through the modification of CD4+ and CD8+ T-cell populations in SMAD-/- mice and that chronic inflammation is the risk factor for colorectal

A meta-analysis of "a global perspective" produced a summary effect estimate of 0.99 (95% CI 0.97-1.00) per 100 IU/day (World Cancer Research Fund, 2007c). Higher vitamin D levels are associated with a lower risk of colon cancer and overall mortality. UV exposure stimulates vitamin D production, but it may increase the risk of skin cancer. Therefore it is recommended that high-risk populations with a low level of vitamin D intake increase the

Vitamin D induces differentiation, apoptosis and induces G1 phase arrest in intestinal cells. It also increases the absorption of calcium in the small and large intestine. Most of the pleiotropic, long-term actions of [1,25 (OH)2D3] are mediated by binding to vitamin D receptors (VDR), which are high-affinity receptors in the nucleus of cells. Activated VDR induces gene transcription, and VDR density in colonic mucosa was higher in hyperplastic polyps and in early stages of carcinogenesis, compared with normal mucosa (Lamprecht &

There was not enough evidence for cancer prevention at the time of when "a grovel Perspective" was drawn up in 2007, so the following foods and nutrition were judged limited-non conclusive: Cereals (grains) and their products, potatoes, poultry, shellfish and other seafood, other dairy products, total fat, fatty acid, cholesterol, sugar (sucrose), coffee, tea, caffeine, total carbohydrate, starch, vitamin A, retinol, vitamin C, vitamin E, multivitamins, non-dairy sources of calcium, methionine, beta-carotene, alpha-carotene,

Some of the latest research has demonstrated new knowledge, or confirmed the previous

consumption of fish, or take vitamin D supplements (Zeeb & Greinert, 2010).

Lipkin, 2001; Lamprecht & Lipkin, 2003; World Cancer Research Fund, 2007c).

2010a; Pot et al., 2010b).

cancer (Woodworth et al., 2010). **2.4.2.5 Foods containing vitamin D** 

**2.4.3 Limited-non conclusive and others** 

lycopene, meal frequency, and energy intake.

2001).

results.

A pooled analysis of cohort studies concluded that a high consumption of vitamin C and E from both food and supplements showed an inverse association with colon cancer risk, although there were some interactions with folate intake. Multivitamin intake also significantly decreases the risk of colon cancer. On the other hand, vitamin A, vitamin C, and vitamin E intake from food only were not associated with colon cancer risk (Park et al., 2010).

In the Caucasian race, a high intake of each anti-oxidant nutrient (vitamin C, vitamin E, βcarotene, selenium) and DNA methylation-related nutrients (folate, vitamin B6, vitamin B12) reduced the risk of distal colorectal cancer, and only selenium showed a lower risk in African Americans. In this study, both intake from food only and total intake (food and supplements) demonstrated cancer prevention potency (Williams et al., 2010).

In colorectal cancer patients, the level of vitamin A, vitamin C, and vitamin E were reduced, and urinary 8-oxo-dG, a biomarker of DNA oxidation, was elevated (Obtulowicz et al., 2010).

A high consumption of carotenoid did not reduce the risk of colorectal cancer, except for βcarotene intake among men, which showed an inverse association (relative risk 0.77, 95% CI 0.763-0.95). On the other hand, lycopene intake was significantly associated with an increase in the risk of rectal cancer among men (relative risk 1.50, 95% CI 1.04-2.16) (Park et al., 2009).

#### **2.4.3.2 Other dietary factors**

Avenanthraide (Avns) polyphenols from oats showed anti-proliferative effects independent of Cox-2 expression in COX-2 positive HT29, Caco-2 and LS174T cells, and COX-2 negative HCT116 cells. Avns may also reduce the colon cancer risk inhibiting PGE2 production derived from macrophage (Guo et al., 2010).

In animal studies, the oral administration of flavone (400mg/kg over 4 weeks) increased apoptosis and reduced the rate of aberrant crypt formation in mice. The down-regulation of the tricarboxylic acid cycle may be a part of the action mechanism (Winkelmann et al., 2010). In a human study, a case-control study of dietary flavonoid showed that flavonoid, especially quercetin, was significantly associated with a reduction in the colorectal cancer risk (Kyle et al., 2010).

In an SD rat study, Coenzyme Q10 reduced the number of APFs, possibly by modulating COX-2 and iNOS gene expression in colonic mucosa, and DNA damage in leukocytes (Kim & Park, 2010).

It has been reported that an increased consumption of n-3 fatty acid, Sulforaphane, Chafuroside, Curcumin and Dibenzoylmethane decreased the number of small intestinal tumors in *Apc*Min mice. On the other hand, there are a few reports on colonic tumor that showed that 31 g/kg of steridonic acid or 600 ppm of sulforaphane demonstrated an inhibitory effect on colonic tumors in *Apc*Min mice (Petrik et al., 2000; Shen et al., 2007).

#### **2.5 The latest proposed action mechanisms**

Various mechanisms, such as DNA repair, proapoptosis, cell cycle modification, immunity promotion, and the mediation of chemomediators, have been proposed as the effects of

Colorectal Cancer and the Preventive Effects of Food Components 221

year low calorie diet in obese people modified the proportion of gut microbes, increasing bacteroidestes and decreasing firmicutes, while obese people had fewer bacteroidetes and

Supplementation employing a drink fortified with short-chain fructooligosaccharides and inulin (1.5 g/day) significantly increased the absorption of calcium in adolescent girls (Griffin et al., 2002). The consumption of oligosaccharides also improved the magnesium absorption in humans and animals (Coudray et al., 2003). An optimum well-tolerated dose of prebiotics might be 10 g/day and a high dose (e.g. > 20 g/day) of some prebiotics might

IGF play important roles in proliferation, differentiation and transfomation in a variety of cell types, and thus it has been suggested that dysregulation of the IGF is an important

A study on colon adenocarcinoma showed that n-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), increased IGFBP-6 in human colon adenocarcinoma Caco-2 cells, and the authors proposed that low IGF-II/IGFBP-6 ratios have resulted in less free IGF-II and a resulting slower proliferation of Caco-2 cells (Roynette et al., 2004). All-trans retinoic acid (tRA) showed an anti-proliferative effect in Caos-2 cells, and it was considered that this was due to a partly increased IGFBP-6

A low-calcemic vitamin D analogus decreased the secretion of IGF-II and suppressed HT-29

Calorie restriction in *Apc*Min mice at the rate of 40% reduced the number of intestinal polyps by 57%, compared with mice fed ad libium. The serum levels of IGF-1 and leptin, and urinary corticosterone output were significantly reduced in the calorie restriction group, compared with that of the ad libium group. Supplementation of freeze-dried fruit and vegetable extract with a diet high in olive oil also reduced the number of polyps, even though this group had a calorie intake of about 90% of ad libium. The supplementation of fruit and vegetables significantly reduced the urinary corticosterone output levels, but did

These results indicate that calorie restriction has a great potency for colon cancer prevention, and a diet in high fruit and vegetable without calorie restriction showed less, but still

Calorie restriction or increased exposure to n-3 fatty acid, sulforaphe, chafrroside, curcumin and dibenzoylmethane reduced the risk of colon cancer, while total fat, a diet high in

However, even considering these interesting results, the frequency of colon polyps in the calorie restriction group and the fruit and vegetable group did not show any significant

calories and all-trans retinoic acid increased the risk (Tammariello & Milner, 2010).

changes, compared with the ad libium group (van Kranen et al., 1998).

not show any effect on the serum levels of IGF-1 and leptin (Mai et al., 2003).

significant, intestinal tumorigenesis preventive effects.

have a laxation effect, such as stool frequency or stool weight (Bouhnik et al., 1999).

firmicutes, compared with a lean control group (Ley et al., 2006).

**2.5.2 IGF regulation** 

cancer risk factor (Park, 2008).

expression (Kim et al., 2002).

**2.5.3 Calorie restriction** 

cell proliferation (Oh et al., 2001).

foods and nutrition. Recently, the focus has been on the prebiotic and probiotic effects, insulin-like growth factor (IGF) regulation, and calorie restriction.

### **2.5.1 Prebiotic and probiotic effects**

Feeding specific food products with a prebiotic effect have been reported to reduce the incidence of tumors and cancers (Roberfroid et al., 2010). There are 100 trillion microbial organisms, called the microbiota, in human adult gut (Davis & Milner, 2009). Carbohydrate and proteolytic fermentation are the two main types of anaerobic fermentation in the gastrointestinal tract (Davis & Milner, 2009, as cited in (McIntosh et al., 1999).

Prebiotics are non-digestible food ingredients which stimulate beneficial gut microbiota (Lim et al., 2005), e.g. inulin and other oligosaccharides, lactulose and resistant starch, such as fructooligosaccharides, inulin, lactulose and galactooligosaccharides (Tuohy et al., 2005). Probiotics are live bacteria found in processed foods or in dietary supplements, e.g. yogurt, cheese, fermented milks, juices, smoothies, cereal, and nutrition bars (Penner et al., 2005; Davis & Milner, 2009). Synbiotics are a combination of a probiotic with a prebiotic. A prebiotic can support the activity of a probiotic (Gibson & Roberfroid, 1995).

Prebiotics must survive acidic conditions in the stomach and resist digestion in the small intestine. Then they need to be selectively fermented, and stimulate beneficial bacteria, usually bifidobacteria or lactobacilli, in the colon (Tuohy et al., 2005). In the randomized, double-blind, placebo-controlled trial for 12 weeks, dietary synbiotics reduced colon cancer risk, through increasing *Bifidobacterium* and *Lactobacillus*, and decreasing *Clostridium perfringens* (Rafter et al., 2007).

A 4-year supplementation regime employing *Lactobacillus casei* decreased the recurrence of atypical colonic polyps (Ishikawa et al., 2005).

Several animal studies and human trials showed that prebiotics, probiotics and synbiotics reduced toxic metabolite production, like caecal β-glucuronidase, nitrate reductase activities and caecal pH, in the gut, resulting in the prevention of colorectal cancer. On the other hand, some human studies denied the beneficial effects of prebiotics (Tuohy et al., 2005).

An increased number of bifidobacteria and/or lactobacilli may also play an important role in DNA protective modification and chemically-induced DNA damage (Tuohy et al., 2005). An increased number of biofidobacteria and/or lactobacilli in the gut may suppress the number or activity of putative enteropathogens such as *Escherichia coli* and *Clostridium perfingens* (Reddy, 1999). Prebiotics may also stimulate protective enzyme activities within the intestinal mucosa or reduce the immune inflammatory response (Burns & Rowland, 2000).

Since prebiotics are mostly oligosaccharides, it is considered that they reduce blood glucose. Increasing glycosylated hemogloin (HbA1c), which is a biomarker of glucose control for diabetes, was associated with an increased risk of colorectal cancer in women (Chan & Giovannucci, 2010). However, the consumption of short-chain fructooligosaccharides did not have a significant affect on the glucose level in blood (Luo et al., 2000).

Transplantation of the gut microflora from normal mice into germ-free recipients resulted in increasing their body fat without increasing food consumption (Bajzer & Seeley, 2006). A 1year low calorie diet in obese people modified the proportion of gut microbes, increasing bacteroidestes and decreasing firmicutes, while obese people had fewer bacteroidetes and firmicutes, compared with a lean control group (Ley et al., 2006).

Supplementation employing a drink fortified with short-chain fructooligosaccharides and inulin (1.5 g/day) significantly increased the absorption of calcium in adolescent girls (Griffin et al., 2002). The consumption of oligosaccharides also improved the magnesium absorption in humans and animals (Coudray et al., 2003). An optimum well-tolerated dose of prebiotics might be 10 g/day and a high dose (e.g. > 20 g/day) of some prebiotics might have a laxation effect, such as stool frequency or stool weight (Bouhnik et al., 1999).
