Abstract
Cancer chemopreventive agent sulforaphane (SFN) and dibenzoylmethane (DBM) showed antitumorigenesis effects in several rodent carcinogenesis models. In this study, we investigated the cancer chemopreventive effects and the underlying molecular mechanisms of dietary administration of SFN and DBM alone or in combination in the ApcMin/+ mice model. Male ApcMin/+ mice (12 per group) at age of 5 weeks were given control AIN-76A diet, diets containing 600 ppm SFN and 1.0% DBM, or a combination of 300 ppm SFN and 0.5% DBM for 10 weeks. Mice were then sacrificed, and tumor numbers and size were examined. Microarray analysis, Western blotting, ELISA, and immunohistochemical staining were done to investigate the underlying molecular mechanisms of cancer chemopreventive effects of SFN and DBM. Dietary administrations of SFN and DBM alone or in combination significantly inhibited the development of intestinal adenomas by 48% (P=0.002), 50% (P=0.001), and 57% (P<0.001), respectively. Dietary administration of 600 ppm SFN and 1.0% DBM also reduced colon tumor numbers by 80% (P=0.016) and 60% (P=0.103), respectively, whereas the combination of SFN and DBM treatment blocked the colon tumor development (P=0.002). Both SFN and DBM treatments resulted in decreased levels of prostaglandin E2 or leukotriene B4 in intestinal polyps or apparently normal mucosa. Treatments also led to the inhibition of cell survival and growth-related signaling pathways (such as Akt and extracellular signal-regulated kinase) or biomarkers (such as cyclooxygenase-2, proliferating cell nuclear antigen, cleaved caspases, cyclin D1, and p21). In conclusion, our results showed that both SFN and DBM alone as well as their combination are potent natural dietary compounds for chemoprevention of gastrointestinal cancers.
Highlights
Colorectal cancer is one of the leading causes of cancer-related mortality in the Western countries and the third most commonNote: Supplementary data for this article are available at Cancer Research Online.Epidemiologic studies indicated that the incidence of colon cancer is inversely correlated with the consumption of fruits and vegetables [3]
Many dietary phytochemicals have been investigated for their colon cancer chemopreventive effects using rodent colorectal cancer models, such as the ApcMin/+ mouse, which mimics the rapid development of adenomatous polyps that affect human familial adenomatous polyposis (FAP) and sporadic colorectal cancer patients with early Apc mutation
Dietary consumption of SFN for 3 weeks at doses of 300 and 600 ppm resulted in significant inhibition of intestinal polyposis by 25% and 48% in the ApcMin/+ mouse model in our previous study [5]
Summary
Epidemiologic studies indicated that the incidence of colon cancer is inversely correlated with the consumption of fruits and vegetables [3]. Many dietary phytochemicals have been investigated for their colon cancer chemopreventive effects using rodent colorectal cancer models, such as the ApcMin/+ mouse, which mimics the rapid development of adenomatous polyps that affect human familial adenomatous polyposis (FAP) and sporadic colorectal cancer patients with early Apc mutation. Sulforaphane (SFN) is one of the major isothiocyanates found as its glucosinolate precursor glucoraphanin in cruciferous vegetables, such as broccoli, and has been shown to possess strong anticancer effect [4]. Our recent short-term SFN chemoprevention study in ApcMin/+ mice showed that it could strongly inhibit the intestinal neoplasia development in this model [5]. DBM could induce human colorectal carcinoma cells COLO 205 apoptosis through coordinative regulation of cyclin D3, Bcl-XL, Bax, and cytochrome c release in vitro [9]
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