Abstract 1613: Delta-tocotrienol delays the progression of pancreatic intraepithelial neoplasia (PanIN) lesions in a conditional KrasG12D mouse model

Abstract

Abstract Background: We have shown that natural vitamin E γ-tocotrienol is the most bioactive tocotrienols in inhibiting the cell proliferation and induction of apoptosis in pancreatic cancer cells as well as in xenograft models. Therefore in this study we evaluated the chronic 12-month feeding of γ-tocotrienol on the prevention of the progression of PanIN lesions in a conditional KrasG12D mouse model. Methods: Offspring of LSLKRASG12D x PDX-1-Cre intercrosses (double positive by genotyping) were randomized to three groups: 1) No treatment (NT), 2) Vehicle (ethanol extracted olive oil, 1.0 ml/kg x 2/ day, PO) and 3) γ-tocotrienol (200 mg/kg x 2/day, PO). The treatment was started at the age of 10 weeks and continued for 12 months. The survival of the mice in three groups was plotted by Kaplan-Meir graph. The pancreas of KRASG12D; PDX-1-Cre mice was analyzed for the presence of murine PanINs. The apoptosis, cell cycle and signaling markers were determined by Western blotting and immunostaining. Results: No significant difference in food intake and body weight gain between γ-tocotrienol and control groups was observed during 12 months feeding. γ-tocotrienol treatment significantly increased survival of mice compared to control groups (p<0.025). Mice fed γ-tocotrienol had a significant delay in the progression of mPanIN lesions. The proportion of mPanIN-3 lesion was significantly decreased (P<0.001), whereas the relative numbers of all other lesions combined were slightly increased in the γ-tocotrienol-fed animals. γ-tocotrienol feeding also inhibited the pMEK and pERK signaling and increased p27Kip1 expression in the pancreatic tumor tissues. The apoptosis markers such as caspase-3, PARP1 cleavage, and Bax expression were increased in tumor tissues of mice treated with γ-tocotrienol compared to controls. NF-κB/p65 and the NF-κB transcriptional targets Bcl-XL was down-regulated by γ-tocotrienol treatment. The ratio of the proapoptotic (Bax) and antiapoptotic (Bcl-XL) proteins was increased almost 4-folds in the pancreatic tumor tissues compared to controls. Conclusion: γ-tocotrienol delays the progression of pancreatic cancer precursor lesions in a preclinical animal model hence warrant it's clinical use for the prevention and treatment of pancreatic cancer in high-risk patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1613. doi:1538-7445.AM2012-1613