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

Abstract

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-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 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.

• Authors: Kazim Husain, Rony A Francois, Teruo Yamauchi, Marta Perez, Said M Sebti, Mokenge P Malafa
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 12 Pg. 2363-72 (Dec 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21971120 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• NF-kappa B
• Deoxycytidine
• Vitamin E
• tocotrienol, delta
• Gemcitabine

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Antioxidants (administration & dosage, pharmacology)
• Carcinoma (drug therapy, metabolism)
• Cell Line, Tumor
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Down-Regulation (drug effects)
• Drug Synergism
• Female
• Humans
• Mice
• Mice, SCID
• Models, Biological
• NF-kappa B (antagonists & inhibitors, metabolism)
• Pancreatic Neoplasms (drug therapy, metabolism)
• Up-Regulation (drug effects)
• Vitamin E (administration & dosage, analogs & derivatives, pharmacology)
• Xenograft Model Antitumor Assays
• Gemcitabine