Chemoprevention against colon cancer by dietary intake of sulforaphane

Abstract

Background: Sulforaphane (SFN), a phytochemical compound, which belongs to isothiocyanates family found in abundance in broccoli sprouts, potently induces a variety of antioxidant enzymes via nrf2-keap1 mediated pathway, thereby protects cells from injury induced by various kinds of oxidative stresses. We have previously shown that SFN protects gastric mucosa from oxidative injury induced by H. pylori infection. SFN also down-regulates histone deacetylase (HDAC) activity, thereby induces apoptosis and inhibits proliferation of tumor cells in variety of tissues. On the other hand, colon cancer has been increasing in Japan. Since numerous epidemiological studies have shown that colon cancer is inversely associated with intake of anti-oxidant vegetables, we examined if dietary SGS prevents colon tumorigenesis in mice, and in human subjects.

Methods:  1. Effects of SFN on Colonic tumorigenesis in Mice Treated with Chemical Carcinogen: Effects of SFN on colonic tumorigenesis were examined in the ICR male mice, pretreated with a chemical carcinogen, azoxymethane (AOM) (15 mg/kg). The AOM-treated mice were fed for 8 weeks with or without sulforaphane glucosinolates (SGS: 2,200 ppm/kg/day), which is a precursor of SFN. Effects of SGS treatment on formation of the microscopic aberrant crypt foci (ACF), and the macroscopic tumors in colonic mucosa were evaluated. 2. Effects of SFN on formation of Colonic Aberrant Crypt Foci (ACF) in patients with colonic adenoma: Effects of intake of raw broccoli sprouts (BS), 50 g/day, which contains 220 mg SGS every other day, for 6 months on changes in the number of ACF in rectal mucosa was examined by colonoscopy in patients with colonic adenoma. 3. Effects of SFN on intestinal microbiota in human subjects:  Effects of dietary intake of raw broccoli sprouts (BS), 20 g/day, which contains 88 mg SGS every other day, for 2 weeks on intestinal microbiota in healthy volunteers was assessed by measuring composition of stool bacteria, using T-RFLP method. In human studies, alfalfa sprouts, which contains no SFN was used as a placebo control.

Results: 1. Daily administration of SGS suppressed formation of microscopic ACF and macroscopic colonic tumors in the AOM-pretreated mice in vivo. 2. Intake of BS for 6 months tended to decrease the number of colonic ACF in patients with colonic adenoma. 3. Intake of BS for 2 weeks increased percentages of Bifidobacterium and Clostridium XVIa, which has been shown to enhance protection of colonic mucosa by increasing butyrate production in colonic lumen.

Conclusions: 1. SFN affords chemoprotection against colonic cancer, presumably by up-regulating nrf2-dependent antioxidant enzymes in normal colonic epithelial cells, and by inducing apoptosis of colonic tumor cells through inhibition of HDAC activity. The present study further suggests that changes in intestinal microbiota by SFN, may play a role in chemoprevention against colon cancer.

Keywords: sulforaphane, colon cancer, chemoprevention, aberrant crypt foci, intestinal microbiota