Abstract 2070: Natural vitamin E delta-tocotrienol combined with gemcitabine prolongs the survival, induces apoptosis, inhibits tumor growth, angiogenesis and oncogenic signaling in a transgenic mouse model of pancreatic cancer.
Authors: Husain Kazim , Centeno Barbara , Perez Marta , Dung-Tsa Chen , Sebti Said M. , Malafa Mokenge P. 
Published: August 2014

Background: Pancreatic cancer, an aggressive and lethal cancer is the fourth leading cause of cancer-related deaths in the United States. Gemcitabine is currently the standard therapeutic agent for advanced pancreatic cancer, but has limited efficacy due to chemoresistance and dose escalation toxicity. We have shown that natural vitamin E δ-tocotrienol is the most bioactive tocotrienols against pancreatic cancer in vitro using pancreatic cancer cells lines as well as in vivo using xenograft models. In this study we evaluated the combination of δ-tocotrienol and gemcitabine on survival, tumor growth, apoptosis, angiogenesis and oncogenic signaling in a transgenic mouse model of pancreatic cancer

Methods: Offspring of LSLKRASG12D x PDX-1-Cre x Trp53R172H intercrosses (triple positive by genotyping) were randomized to 4 groups: 1) Vehicle (olive oil, 1.0 ml/kg x 2/ day, PO and PBS 1.0 ml/kg x 2/week, IP), 2) Gemcitabine (100 mg/kg, x 2/week, IP), 3) δ-tocotrienol (200 mg/kg x 2/day, PO) and 4) Gemcitabine + δ-tocotrienol. The treatment was started at the age of 5 weeks and continued for 12 weeks. The survival of the mice in three groups was plotted by Kaplan-Meir graph. The weights of mice were recorded every week and the tumor weights were recorded at the end of the study. The apoptosis markers in plasma and pancreatic tumor, epithelial to mesenchymal transition (EMT), angiogenesis and kras/p53 signaling markers were determined by ELISA, Western blotting and immunostaining.

Results: No significant difference in food intake and body weight gain between drug treatment and control groups was observed. δ-tocotrienol treatment alone significantly increased overall survival compared to vehicle (P&lt;0.01). Gemcitabine slightly increased survival whereas combination of two drugs significantly enhanced survival (P&lt;0.05).

The tumor weights were more significantly decreased in the combination group (p&lt;0.001) than in each drug alone groups (p&lt;0.02). Gemcitabine and δ-tocotrienol alone and in combination decreased EMT (E-cadherin to vimentin) in tumor tissues. Gemcitabine and δ-tocotrienol combination profoundly induced apoptosis (increased CK18 in plasma), PARP1 cleavage, and Bax expression in tumor tissues than either drug alone. δ-tocotrienol was more effective than gemcitabine in the induction of cyclin-dependent kinase inhibitors (p27Kip1 and p21Cip1), inhibition of angiogenesis (VEGF), vascularity (CD31) and Kras down stream signaling (pAKT. pMEK and pERK). However the combination exerted synergistic effect on the above parameters.

Conclusion: δ-tocotrienol synergizes with gemcitabine to inhibit pancreatic tumor growth through inhibition of angiogenesis, cell cycle, Kras signaling and induction of apoptosis in transgenic mouse model of pancreatic cancer.

Citation Format: Kazim Husain, Barbara Centeno, Marta Perez, Chen Dung-Tsa, Said M. Sebti, Mokenge P. Malafa. Natural vitamin E delta-tocotrienol combined with gemcitabine prolongs the survival, induces apoptosis, inhibits tumor growth, angiogenesis and oncogenic signaling in a transgenic mouse model of pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2070. doi:10.1158/1538-7445.AM2013-2070