Combination of Selenium and Green Tea Improves the Efficacy of Chemoprevention in a Rat Colorectal Cancer Model by Modulating Genetic and Epigenetic Biomarkers

Abstract

Dietary supplementation of selenium and green tea holds promise in cancer prevention. In this study, we evaluated the efficacies of selenium and green tea administered individually and in combination against colorectal cancer in an azoxymethane (AOM)-induced rat colonic carcinogenesis model and determined the underlying mechanisms of the protection. Four-week old Sprague-Dawley male rats were fed with diets containing 0.5% green tea extract, 1ppm selenium as selenium-enriched milk protein, or combination of 1ppm selenium and 0.5% green tea extract. Animals received 2 AOM (15 mg/kg) treatments to induce colonic oncogenesis. Rats were killed 8 or 30 wk later after the last AOM to examine the effect of dietary intervention on aberrant crypt foci (ACF) formation or tumor development. On sacrifice, colons were examined for ACF and tumors, the mRNA levels of SFRP5 and Cyclin D1, and the proteins levels of ß-catenin, COX-2, Ki-67, DNMT1 and acetyl histone H3. The combination of selenium and green tea resulted in a significant additive inhibition of large ACF formation, this effect was greater than either selenium or green tea alone, P<0.01; the combination also had a significant additive inhibition effect on all tumor endpoints, the effect of the combination diet on tumor incidence, multiplicity and size was greater than selenium or green tea alone, P<0.01. Rats fed the combination diet showed marked reduction of DNMT1 expression and induction of histone H3 acetylation, which were accompanied by restoration of SFRP5 mRNA in normal-appearing colonic crypts. The combination diet also significantly reduced ß-catenin nuclear translocation, Cyclin D1 expression and cell proliferation. These data show, for the first time, that combination of selenium and green tea is more effective in suppressing colorectal oncogenesis than either agent alone. The preventive effect is associated with regulation of genetic and epigenetic biomarkers implicated in colonic carcinogenesis.

Histone and Non-Histone Targets of Dietary Deacetylase Inhibitors

“…Recently, the combination of EGCG and sodium butyrate was shown to efficiently induce Survivin expression in colon cancer cells 217 . Further, the combination of selenium compounds and green tea extract showed improved anticancer activity in vitro and in vivo 218 . These reports likely represent an incomplete view of all such studies in the literature, but they provide illustrative examples for future work on combination treatments through rational design.…”

Consumption of the total Western diet differentially affects the response to green tea in rodent models of chronic disease compared to the AIN93G diet

“…We chose green tea extract (GTE) as a model bioactive based on known beneficial effects on colorectal cancer (CRC) [5][6][7][8][9][10][11][12][13][14], body composition [15][16][17][18], and hepatic lipid metabolism [19][20][21]. We hypothesized that mice fed a basal diet that emulates the Western dietary pattern would respond differently to the well-known effects of GTE compared to mice fed a diet optimized for growth and health.…”

Diet-Based Strategies for Cancer Chemoprevention: The Role of Combination Regimens Using Dietary Bioactive Components

“…Aberrant methylation frequently reported in colorectal cancer was unaffected by the combination of isothiocyanates and selenium in Caco-2 and HCT116 colon cancer cells (Barrera et al 2013). In contrast, a marked reduction of abnormal methylation was indicated with decreased expression of DNA methyltransferase-1 (DNMT1) following green-tea-plus-selenium combination treatment in a rat colorectal cancer model (Hu et al 2013). Interestingly, the same combination also exhibited a greater induction of histone H3 acetylation than green tea or selenium alone, an important finding as deacetylated histone H3 has been positively associated with colorectal cancer development.…”