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

Abstract

ObjectivesColorectal 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. MethodsWe 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. ResultsIn 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. ConclusionsDietary supplementation of δTE/γTE is promising chemoprevention against sporadic colorectal tumor development. Funding SourcesThe authors gratefully acknowledge the support of USDA Hatch fund, Research Awards from the Purdue Center for Cancer Research, and NIH grant.