Prolonged survival and delayed progression of pancreatic intraepithelial neoplasia in LSL-KrasG12D/+;Pdx-1-Cre mice by vitamin E δ-tocotrienol

The highly lethal nature of pancreatic cancer and the increasing recognition of high-risk individuals have made research into chemoprevention a high priority. Here, we tested the chemopreventive activity of -tocotrienol, a bioactive vitamin E derivative extracted from palm fruit, in the LSL-Kras(G12D/);Pdx-1-Cre pancreatic cancer mouse model. At 10 weeks of age, mice (n 92) were randomly allocated to three groups: (i) no treatment; (ii) vehicle and (iii) -tocotrienol (200mg/kg 2/day, PO). Treatment was continued for 12 months. Mice treated with -tocotrienol showed increased median survival from the onset of treatment (11.1 months) compared with vehicle-treated mice (9.7 months) and non-treated mice (8.5 months; P < 0.025). Importantly, none of the mice treated with -tocotrienol harbored invasive cancer compared with 10% and 8% in vehicle-treated and non-treated mice, respectively. Furthermore, -tocotrienol treatment also resulted in significant suppression of mouse pancreatic intraepithelial neoplasm (mPanIN) progression compared with vehicle-treated and non-treated mice: mPanIN-1: 4750% (P < 0.09), mPanIN-2: 611% (P < 0.001), mPanIN-3: 315% (P < 0.001) and invasive cancer: 010% (P < 0.001). -Tocotrienol treatment inhibited mutant Kras-driven pathways such as MEK/ERK, PI3K/AKT and NF-kB/p65, as well as Bcl-xL and induced p27. -Tocotrienol also induced biomarkers of apoptosis such as Bax and activated caspase 3 along with an increase in plasma levels of CK18. In summary, -tocotrienols ability to interfere with oncogenic Kras pathways coupled with the observed increase in median survival and significant delay in PanIN progression highlights the chemopreventative potential of -tocotrienol and warrants further investigation of this micronutrient in individuals at high risk for pancreatic cancer.