Preclinical Development Vitamin E d-Tocotrienol Augments the Antitumor Activity of Gemcitabine and Suppresses Constitutive NF-kB Activation in Pancreatic Cancer

The NF-kB transcription factor functions as a crucial regulator of cell survival and chemoresistance in pancreatic cancer. Recent studies suggest that tocotrienols, which are the unsaturated forms of vitamin E, are a promising class of anticancer compounds that inhibit the growth and survival of many cancer cells, including pancreatic cancer. Here, we show that tocotrienols inhibited NF-kB activity and the survival of human pancreatic cancer cells in vitro and in vivo. Importantly, we found the bioactivity of the four natural tocotrienol compounds (a-, b-, d-, and g-tocotrienol) to be directly related to their ability to suppressNF-kB activity in vitro and in vivo. The most bioactive tocotrienol for pancreatic cancer, d-tocotrienol, significantly enhanced the efficacy of gemcitabine to inhibit pancreatic cancer growth and survival in vitro and in vivo. Moreover, we found that d-tocotrienol augmentation of gemcitabine activity in pancreatic cancer cells and tumors is associated with significant suppression of NF-kB activity and the expression of NF-kB transcriptional targets (Bcl-XL, X-linked inhibitor of apoptosis, and survivin).Our study represents the first comprehensivepreclinical evaluation of the activity of natural vitamin E compounds in pancreatic cancer. Given these results, we are conducting a phase I trial of d-tocotrienol in patients with pancreatic cancer using pancreatic tumor cell survival and NF-kB signaling components as intermediate biomarkers. Our data also support future clinical investigation of d-tocotrienol to augment gemcitabine activity in pancreatic cancer. Mol Cancer Ther; 10(12); 2363–72. 2011 AACR.