Vitamin E δ-Tocotrienol Augments the Antitumor Activity of Gemcitabine and Suppresses Constitutive NF-κB Activation in Pancreatic Cancer

Abstract

The nuclear factor-κB (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 anti-cancer 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 4 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 (XIAP), and survivin]. Our study represents the first comprehensive pre-clinical 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 utilizing 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.

Vitamin E δ-Tocotrienol Prolongs Survival in the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) Transgenic Mouse Model of Pancreatic Cancer

“…One intriguing finding that has been demonstrated consistently by us and others is the selective killing effect of VEDT against cancer cells (12, 14, 32, 33). We have also demonstrated selective induction of apoptosis by VEDT of pancreatic transformed and malignant epithelial cells but not normal immortalized human pancreatic ductal epithelial cells (12, 32). Other anticancer effects of tocotrienol include the inhibition of cell migration and invasion and the inhibition of angiogenesis (21, 24, 34).…”

“…Earlier studies have shown in vitro using pancreatic cancer cell lines and in vivo using a xenograft mouse model and conditional Kras G12D mouse model that VEDT inhibits cell survival, including oncogenic Kras signaling (12, 14, 26–28). Here, we investigated the effect of VEDT on Kras signaling and cell cycle proteins.…”

“…The NF-kB transcription factor functions as a crucial regulator of cell survival and chemoresistance in pancreatic cancer (11, 38). We have shown in vitro as well as in vivo studies that VEDT targets the transcription factor NF-kB signaling, a pro survival pathway (12, 14). Inhibition of constitutively active NF-kB resulted in the depletion of NF-kB–regulated gene products such as cell survival anti-apoptotic proteins (BCl-XL, XIAP, and cFLIP) favoring the induction of caspases (-8, -9 and -3) leading to both extrinsic and intrinsic pathways of apoptosis.…”

“…Tocotrienols are unsaturated, naturally occurring vitamin E compounds, which exist as four isoforms: α-, β-, δ-, and γ-tocotrienol (11). We have shown that, for pancreatic cancer, vitamin E δ-tocotrienol (VEDT) is the most potent anticancer agent among the four isomers, both in vitro and in vivo (12). We have also shown that oral administration of 100 mg/kg/day of VEDT to mice resulted in satisfactory bioavailability in mouse pancreas tissue with no significant toxicity (13).…”

Effect of NF-κB inhibition on chemoresistance in biliary–pancreatic cancer

“…Curcumin (diferuloylmethane), a derivative of the spice turmeric, potentiates the chemosensitivity of gemcitabine by inhibiting IκBα phosphorylation [43]. Meanwhile, tocotrienols, naturally occurring unsaturated vitamin E compounds, augment the antitumor activity of gemcitabine by suppressing the phosphorylation of IκBα [44]. Honokiol, a biologically active biphenolic compound isolated from Magnolia officinalis/grandiflora, also potentiates the cytotoxicity of gemcitabine by inducing G1-phase cell cycle arrest and suppressing IκBα phosphorylation [45].…”