PT  - JOURNAL ARTICLE
AU  - Husain, Kazim
AU  - Francois, Rony A.
AU  - Yamauchi, Teruo
AU  - Perez, Marta
AU  - Sebti, Said M.
AU  - Malafa, Mokenge P.
TI  - Vitamin E δ-Tocotrienol Augments the Antitumor Activity of Gemcitabine and Suppresses Constitutive NF-κB Activation in Pancreatic Cancer
AID  - 10.1158/1535-7163.MCT-11-0424
DP  - 2011 Dec 01
TA  - Molecular Cancer Therapeutics
PG  - 2363--2372
VI  - 10
IP  - 12
4099  - http://mct.aacrjournals.org/content/10/12/2363.short
4100  - http://mct.aacrjournals.org/content/10/12/2363.full
SO  - Mol Cancer Ther2011 Dec 01; 10
AB  - The NF-κB 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-κB 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 (α-, β-, δ-, and γ-tocotrienol) to be directly related to their ability to suppress NF-κB activity in vitro and in vivo. The most bioactive tocotrienol for pancreatic cancer, δ-tocotrienol, significantly enhanced the efficacy of gemcitabine to inhibit pancreatic cancer growth and survival in vitro and in vivo. Moreover, we found that δ-tocotrienol augmentation of gemcitabine activity in pancreatic cancer cells and tumors is associated with significant suppression of NF-κB activity and the expression of NF-κB transcriptional targets (Bcl-XL, 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 δ-tocotrienol in patients with pancreatic cancer using pancreatic tumor cell survival and NF-κB signaling components as intermediate biomarkers. Our data also support future clinical investigation of δ-tocotrienol to augment gemcitabine activity in pancreatic cancer. Mol Cancer Ther; 10(12); 2363–72. ©2011 AACR.