The NF-kappaB 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-kappaB 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 (alpha-, beta-, delta-, and gamma-tocotrienol) to be directly related to their ability to suppress NF-kappaB activity in vitro and in vivo. The most bioactive tocotrienol for pancreatic cancer, delta-tocotrienol, significantly enhanced the efficacy of gemcitabine to inhibit pancreatic cancer growth and survival in vitro and in vivo. Moreover, we found that delta-tocotrienol augmentation of gemcitabine activity in pancreatic cancer cells and tumors is associated with significant suppression of NF-kappaB activity and the expression of NF-kappaB transcriptional targets (Bcl-X(L), X-linked inhibitor of apoptosis, and survivin). Our study represents the first comprehensive preclinical evaluation of the activity of natural vitamin E compounds in pancreatic cancer. Given these results, we are conducting a phase I trial of delta-tocotrienol in patients with pancreatic cancer using pancreatic tumor cell survival and NF-kappaB signaling components as intermediate biomarkers. Our data also support future clinical investigation of delta-tocotrienol to augment gemcitabine activity in pancreatic cancer.
