Low doses of β‐carotene and lutein inhibit AOM‐induced rat colonic ACF formation but high doses augment ACF incidence

Abstract

Epidemiological studies suggest that carotenoids such as ␤-carotene and lutein play an important role in reducing the risk for several cancers. However, in colon cancer there is ambiguity with regard to the role of these compounds in that both preventive effects and tumor promotion have been observed. In the present study we observed that male F344 rats were able to tolerate up to 2,500 ppm of ␤-carotene as well as of lutein. We have then assessed the chemopreventive efficacy of ␤-carotene and lutein at dose levels of ϳ4 and 8% of the 2,500 ppm tolerated dose (TD) and also ϳ40 and 80% of the TD on azoxymethane (AOM)-induced colon carcinogenesis, using aberrant crypt foci (ACF) as a surrogate biomarker for colon cancer. Throughout the experiments, 5-weekold male F344 rats were fed the control diet (modified AIN-76A) or experimental diets containing 100 or 200 ppm (ϳ4 or 8% of the 2,500 ppm TD), or 1,000 or 2,000 ppm (ϳ40 or 80% of the 2,500 ppm TD) of ␤-carotene and lutein (n‫01؍‬ rats/group). After 2 weeks on the experimental or control diets, all animals were injected with AOM (15 mg/kg body wt., once weekly for 2 weeks). At 14 weeks of age, all rats were killed, and their colons were evaluated for ACF. Administration of 100 or 200 ppm of ␤-carotene inhibited AOM-induced total colonic ACF formation by 24% (p<0.01) and 36% (p<0.001), respectively, whereas lutein at 200 ppm produced a 27% inhibition (p<0.01) yet had no significant effect at the 100 ppm dose level. Surprisingly, administration of 1,000 or 2,000 ppm of ␤-carotene and lutein increased colonic ACF formation in a dose-dependent manner, i.e., to 124% and 144% for the former and 110% and 159% for the latter. These results clearly suggest that further studies are warranted to determine whether the increase in ACF incidence by high doses of ␤-carotene and lutein will also lead to an increase in tumor outcome. Taken together these data indicate that the chemopreventive activity of ␤-carotene and lutein against colon carcinogenesis depends on the dose level. © 2004 Wiley-Liss, Inc. Key words: colon cancer; aberrant crypt foci; chemoprevention; ␤-carotene; lutein Colorectal cancer is one of the leading causes of cancer deaths in both men and women in Western countries, including the United States. 1 Evidence from epidemiological studies and laboratory animal assays suggests a relationship between colon cancer risk and several dietary factors. 2,3 Identification of naturally occurring carcinogens and anti-carcinogens should lead not only to an understanding of carcinogenesis but should also provide strategies for cancer prevention. Several epidemiological studies have consistently demonstrated that people who have a high intake of vegetables and fruits that are rich in carotenoids had low risk of cancer. 4 -7 Possible cancer preventive effects of carotenoids have been established in several epidemiological and clinical studies by comparing serum levels of carotenoids in normal and cancer patients. 8 -10 Some studies also pointed to a possible relationshi...

β-Ionone inhibits colonic aberrant crypt foci formation in rats, suppresses cell growth, and induces retinoid X receptor-α in human colon cancer cells

“…This confirms the safe usage of h-ionone at the doses we evaluated. Unlike our previous observations with carotenoids, h-ionone was observed to be effective in inhibiting ACF even at 0.1% and 0.2% dose levels (40). In the present study, administration of h-ionone provided up to 38% inhibition of azoxymethane-induced total ACF formation and suppression of four or more crypts growth up to z55%, which clearly suggests the potential colon tumor inhibitory properties of h-ionone (Fig.…”

S‐adenosyl L‐methionine inhibits azoxymethane‐induced colonic aberrant crypt foci in F344 rats and suppresses human colon cancer Caco‐2 cell growth in 3D culture

“…26,27 ACF has been widely used as a surrogate biomarker to study the effect of dietary factors or nutritional supplements on colon cancer carcinogenesis in AOM-induced F344 rats. [28][29][30] In the present study, we therefore, investigated the impact of SAM on ACF formation in the F344 rat colon. We also studied the effect of SAM on COX-2 expression in a macrophage RAW cell line.…”

Chemoprevention of aberrant crypt foci in the colon of rats by dietary onion

“…We do not think, however, that these differences could account for the discrepancy between studies results. In contrast, we think that an agent may be beneficial at a low level, but "too much of a good thing" may be detrimental, as suspected also for beta-carotene and folic acid (15,16).…”