Abstract 5416: Delta-tocotrienol potentiates antitumor activity of gemcitabine in pancreatic cancer through inhibition of nuclear factor-κB (2010)

Abstract Background: Gemcitabine is currently the standard therapeutic agent for advanced pancreatic cancer, but has limited efficacy due to chemoresistance. Chemoresistance to gemcitabine seems to be due to constitutive activation of nuclear factor-kappaB (NF-κB) and induction of its regulated gene products. We have already shown that δ-tocotrienol is the most active natural vitamin E in depleting the NF-κB activity in pancreatic cancer. Therefore in this study we used δ-tocotrienol to enhance the antitumor activity of gemcitabine in pancreatic cancer in vitro and in vivo. Methods: The antiproliferative (MTT assay) and proapoptotic (Cell Death ELISA assay) activities of gemcitabine and δ-tocotrienol alone and in combination were evaluated in human pancreatic cancer cell lines MiaPaCa-2 and AsPc-1. Additive/synergistic effects of the combination was determined using combination index and isobologram plot. The effect of the two drugs and combination on malignant transformation in MiaPaca-2 cells was determined by colony formation assay. The in vivo activity of the two drugs and combination was evaluated in SCID nude mice xenografted with AsPc-1 cells. Because the NF-κB has a central role in gemcitabine chemoresistance, we investigated the effect of the two drugs alone and in combination on the NF-κB activity and its regulated gene products in vitro and in vivo. Results: The combination of gemcitabine and δ-Tocotrienol inhibited the cell proliferation of pancreatic cancer cells (AsPc-1 and Mia PaCa-2) more than either drug alone. Gemcitabine and δ-tocotrienol combination at 1:2 ratio resulted in additive to synergistic effects on inhibition of cell proliferation of Mia PaCa-2 cells. The inhibition of malignant transformation and apoptosis induction (histone associated DNA fragments, caspase-3 activity, PARP-1 cleavage, and BAX expression) in pancreatic cancer cells was greater with δ-tocotrienol compared with gemcitabine. The combination of the two drugs resulted in additive/synergistic effects on apoptosis induction. Gemcitabine and δ-tocotrienol combination was more effective in inhibiting AsPc-1 tumor growth and apoptosis induction in mice than either drug alone. Gemcitabine was less effective in inhibiting the nuclear DNA binding of NF-κB/p65 activity, p65/p50 subunits, and antiapototic proteins Bcl-XL, XIAP and survivin expression compared to δ-tocotrienol. However the combination of gemcitabine and δ-Tocotrienol showed additive/synergistic effects on depletion of NF-κB activity and its regulated gene products in vitro and in vivo. Conclusion: This combination chemotherapy could be a potential novel strategy for advanced pancreatic cancer. This study supports the selection of δ-tocotrienol as a potential therapeutic adjuvant to potentiate gemcitabine antitumor activity in human pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5416.