title: 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.affiliation: Department of Gastrointestinal Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
authors.forename: Kazim
authors.initials: K
authors.lastname: Husain
authors.forename: Rony A
authors.initials: RA
authors.lastname: Francois
authors.forename: Teruo
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Marta
authors.initials: M
authors.lastname: Perez
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Mokenge P
authors.initials: MP
authors.lastname: Malafa
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000975:Antioxidants; D016328:NF-kappa B; D003841:Deoxycytidine; D014810:Vitamin E; C082097:tocotrienol, delta; D000093542:Gemcitabine