Sesame, which has been reported to have preventive effects against various disordered conditions, contains small quantities of lignans and several precursors to them such as sesaminol glucosides (SG). The lignans have the potent antioxidative activity and are suggested to have chemopreventive property. In the present study, we evaluated the modulating effect of SG on the development of colon precancerous lesions, aberrant crypt foci (ACF) and beta-catenin-accumulated crypts (BCAC), in the azoxymethane (AOM)-induced short-term model using male F344 rats. Dietary SG (500 ppm) significantly decreased the incidence of AOM-induced ACF when compared to the control (P<0.01). The incidences of AOM-induced BCAC in the SG-treated groups (250 or 500 ppm) were also significantly lower than that of the control group (P<0.01). Interestingly, administration of 500 ppm SG clearly decreased serum triglyceride level and mRNA expression of intestinal fatty acid-binding protein in the colonic mucosa, as compared to the control. These findings indicate that dietary SG inhibits AOM-induced carcinogenesis and suggest SG as a possible chemopreventive agent.

9-cis-Retinoic acid (9cRA) binds both retinoic acid receptors (RARs) and retinoid X receptors (RXRs) and has been shown to be a potential chemopreventive agent both in lung cancer cell culture studies and in clinical trials studying former smokers. However, direct evidence of the efficacy of 9cRA against lung tumor development in vivo is lacking. In the present study, we determined whether treatment with 9cRA has the potential to inhibit lung carcinogenesis by upregulating RAR-beta and down-regulating COX-2 expression in the A/J mouse lung cancer model. A/J mice (n=14-15/group) were treated as follows: (1) Control (Sham treated); (2) NNK (100mg NNK/kg body weight); (3) NNK+9cRA (15mg/kg diet); and (4) NNK+celecoxib (a COX-2-specific inhibitor, 500mg/kg diet). Tumor incidence, tumor multiplicity, RAR-beta mRNA, COX-2 mRNA, and COX-2 protein levels in lung samples of mice were determined 4 months after carcinogen injection. The results showed that mice receiving 9cRA supplementation had significantly lower tumor multiplicity (48% reduction, P<0.05) and showed a trend toward lower tumor incidence (40% reduction, P=0.078), as compared with the mice given NNK alone. Although, celecoxib treatment resulted in greater declines in tumor incidence and tumor multiplicity (75 and 88%, respectively, P<0.05), the chemoprotective effects of celecoxib were accompanied by increased mortality while 9cRA treatment resulted in no weight-loss associated toxicity or mortality. Supplementation with 9cRA was effective in increasing RAR-beta mRNA, but this increase was not accompanied by decreased levels of COX-2 mRNA or protein. These results suggest that 9cRA supplementation may provide protection against lung carcinogenesis and this effect may be mediated in part by 9cRA induction of RAR-beta, but not inhibition of COX-2 transcription.

Disruption of the DNA mismatch repair (MMR) pathway results in elevated mutation rates, inappropriate survival of cells bearing DNA damage, and increased cancer risk. Relatively little is known about the impact of environmentally relevant carcinogens on cancer risk in individuals with MMR-deficiency. We evaluated the effect of MMR status (Mlh1(+/+) versus Mlh1(-/-)) on the carcinogenic potential of the cooked-meat mutagen, 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) in mice. PhIP exposure did not obviously increase lymphoma or small intestinal tumorigenesis in either Mlh1-deficient or -proficient mice. In contrast, the frequency of aberrant crypt foci (ACF), a preneoplastic biomarker for colon tumorigenesis, was increased by PhIP, and the increase due to PhIP was significantly greater in Mlh1(-/-) versus wild-type littermates. This apparent heightened susceptibility to induction of ACF parallels the previously reported hypermutability of Mlh1-deficient mice to PhIP and is consistent with the hypothesis that MMR-deficiency would increase the likelihood of PhIP-induced carcinogenic mutations. Further evaluation of the risk that consumption of heterocyclic amines may impart to MMR-deficient individuals therefore is warranted.

Esophageal cancer is common worldwide, with poor prognosis. Smoking, including exposure to polyaromatic hydrocarbons like benzo[a]pyrene (BaP), is a major risk factor. In human esophageal HET-1A cells, we found that time-dependent BaP-DNA binding was associated with upregulation of CYP1B1, but not CYP1A1, mRNA and protein. The dietary flavonoid 5,7-dimethoxyflavone significantly inhibited BaP-DNA binding and down-regulated BaP-induced CYP1B1 mRNA and protein. 3',4'-Dimethoxyflavone was an even more potent inhibitor of CYP1B1 expression, while resveratrol had no effect. Thus, dietary methoxylated flavones inhibited BaP-induced CYP1B1 transcription in a cell-specific manner and hold promise as chemopreventive agents in esophageal carcinogenesis.