Chemopreventive Effects of Delta-tocotrienol (δTE) in a Mouse Model Bearing Key Genetic Mutations Resembling Sporadic Colorectal Cancer

OBJECTIVES: Colorectal cancer (CRC) is the third most common cancer in the United States and worldwide. Since there is no effective treatment of late-stage cancer, chemoprevention is an important strategy to reduce cancer motality. Most CRCs occur sporadically and are caused by somatic gene mutations. Nearly 80% of sporadic CRC patients have alteration in the adenomatous polyposis coli (APC) and about 40–50% have oncogenic mutation in Kirsten rat sarcoma viral oncogene homologue (KRAS), which fosters uncontrolled cell proliferation. Delta-tocotrienol (δTE) is a natural vitamin E form, and has been shown to have potent anti-inflammatory and anti-cancer activities. However, the anti-cancer effect of δTE has not been tested in a preclinical model that resembles sporadic CRC. The objective of this study is to examine the effect of dietary supplementation of δTE on tumorigenesis in a genetically-engineered mouse model resembling sporadic CRC. METHODS: We bred AKC mice which were created by tissue specific inactivation of Apc and oncogenic activation of mutant Kras in the large intestine. In study 1, 5-week-old mice were given control (AIN-93G) or 0.04% δTE/γTE (8/1, v/v) in AIN-93G diet for 10 weeks and their impact on the survival rate was analyzed. In study 2, to further examine chemopreventive effect of δTE, 4.5-week-old mice were given either control or 0.04% δTE/γTE (8/1, v/v) in AIN-93G diet for 4 weeks, and the effect on tumor development and relevant endpoints were evaluated. RESULTS: In study 1, dietary supplementation of δTE/γTE increased the survival of the AKC mice compared with the control diet group (95 ± 4.8 Vs. 76.5 ± 5.0 days, Mean ± SE, p < 0.05). In study 2, δTE/γTE supplementation for four weeks significantly reduced the number of large tumors and total tumor area. These anticancer effects were associated with lowered level of interleukin (IL)-1β in the colon tissue when compared with the control group. Pathway analyses of RNA-seq data showed that δTE/γTE supplement had significant impact on lipid metabolism and enhanced negative regulator of RAS/MAPK pathway. CONCLUSIONS: Dietary supplementation of δTE/γTE is promising chemoprevention against sporadic colorectal tumor development. FUNDING SOURCES: The authors gratefully acknowledge the support of USDA Hatch fund, Research Awards from the Purdue Center for Cancer Research, and NIH grant.