Abstract 1699: Delta-tocotrienol potentiates the antitumor activity of standard chemotherapy with gemcitabine and abraxane in metastatic pancreatic cancer

Abstract

Abstract 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 chemotherapeutic agent for advanced pancreatic cancer, but has limited efficacy due to chemoresistance and dose escalation toxicity. Recently Abraxane has been approved for metastatic pancreatic cancer along with gemcitabine. We have shown that natural vitamin E δ-tocotrienol is the most bioactive tocotrienols against pancreatic cancer in vitro as well as in vivo models. The purpose of this study was to evaluate the combination of δ-tocotrienol, gemcitabine and abraxane on anchorage-dependent and indepencent metastatic tumor cell growth, EMT, apoptosis, angiogenesis and oncogenic signaling in metastatic human pancreatic cancer cell L3.6pl. Methods: Human pancreatic cancer cell MiaPaCa-2 and human metastatic pancreatic cancer cell L3.6pl were treated with different concentrations of δ-tocotrienol (10-100 μM), gemcitabine (0.5-10 μM) and abraxane (0.5-10 μM) alone and in combination and anchorage-dependent growth recorded using MTT assay for 72 h. The effect of δ-tocotrienol, gemcitabine and abraxane alone and in combination on anchorage independent growth were performed using soft agar colony formation assay. The apoptosis markers, epithelial to mesenchymal transition (EMT), angiogenesis and oncogenic signaling markers were determined by Western blotting. Results: Abraxane, gemcitabine and δ-tocotrienol alone significantly inhibited the anchorage-dependent growth in a concentration dependent manner. The combination of the two drugs inhibited the growth synergistically. However the combination of the three drugs profoundly inhibited the cell growth. Abraxane, gemcitabine and δ-tocotrienol alone inhibited the soft agar colony formation but when δ-tocotrienol was combined with gemcitabine and abraxane almost completely inhibited the malignant transformation or anchorage independent cell growth. Abraxane, gemcitabine and δ-tocotrienol alone induced apoptosis (cleaved PARP1 and Bax expression) but when δ-tocotrienol was combined with gemcitabine and abraxane profoundly increased apoptosis. Abraxane, gemcitabine and δ-tocotrienol alone slightly decreased EMT (E-cadherin to vimentin), angiogenesis (VEGF), pAKT and induction of cyclin-dependent kinase inhibitor (p27Kip1) but when δ-tocotrienol was combined with gemcitabine and abraxane profoundly decreased EMT, angiogenesis and pAKT and more induction of p27Kip1. Conclusion: δ-tocotrienol potentiates antitumor activity of gemcitabine and abraxane through inhibition of metastatic pancreatic tumor growth, EMT, angiogenesis, cell cycle, oncogenic signaling and induction of apoptosis in human metastatic pancreatic cancer. Citation Format: Kazim Husain, Said M. Sebti, Mokenge P. Malafa. Delta-tocotrienol potentiates the antitumor activity of standard chemotherapy with gemcitabine and abraxane in metastatic pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1699. doi:10.1158/1538-7445.AM2014-1699