Vitamin E ?-tocotrienol augments the antitumor activity of gemcitabine and suppresses constitutive NF-?B activation in pancreatic cancer.

ABSTRACT: The NF-?B 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-?B 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 (?-, ?-, ?-, and ?-tocotrienol) to be directly related to their ability to suppress NF-?B activity in vitro and in vivo. The most bioactive tocotrienol for pancreatic cancer, ?-tocotrienol, significantly enhanced the efficacy of gemcitabine to inhibit pancreatic cancer growth and survival in vitro and in vivo. Moreover, we found that ?-tocotrienol augmentation of gemcitabine activity in pancreatic cancer cells and tumors is associated with significant suppression of NF-?B activity and the expression of NF-?B 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 ?-tocotrienol in patients with pancreatic cancer using pancreatic tumor cell survival and NF-?B signaling components as intermediate biomarkers. Our data also support future clinical investigation of ?-tocotrienol to augment gemcitabine activity in pancreatic cancer.

SUBMITTER: Husain K 

PROVIDER: S-EPMC3237822 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature