title: δ-Tocotrienol, a natural form of vitamin E, inhibits pancreatic cancer stem-like cells and prevents pancreatic cancer metastasis.
abstract: The growth, metastasis, and chemotherapy resistance of pancreatic ductal adenocarcinoma (PDAC) is characterized by the activation and growth of tumor-initiating cells in distant organs that have stem-like properties. Thus, inhibiting growth of these cells may prevent PDAC growth and metastases. We have demonstrated that δ-tocotrienol, a natural form of vitamin E (VEDT), is bioactive against cancer, delays progression, and prevents metastases in transgenic mouse models of PDAC. In this report, we provide the first evidence that VEDT selectively inhibits PDAC stem-like cells. VEDT inhibited the viability, survival, self-renewal, and expression of Oct4 and Sox2 transcription factors in 3 models of PDAC stem-like cells. In addition, VEDT inhibited the migration, invasion, and several biomarkers of epithelial-to-mesenchymal transition and angiogenesis in PDAC cells and tumors. These processes are critical for tumor metastases. Furthermore, in the L3.6pl orthotopic model of PDAC metastases, VEDT significantly inhibited growth and metastases of these cells. Finally, in an orthotopic xenograft model of human PDAC stem-like cells, we showed that VEDT significantly retarded the growth and metastases of gemcitabine-resistant PDAC human stem-like cells. Because VEDT has been shown to be safe and to reach bioactive levels in humans, this work supports investigating VEDT for chemoprevention of PDAC metastases.
authors.affiliation: Departments of Gastrointestinal Oncology, Tampa, FL, USA.
authors.forename: Kazim
authors.initials: K
authors.lastname: Husain
authors.affiliation: Departments of Pathology, Tampa, FL, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Centeno
authors.affiliation: Departments of Pathology, Tampa, FL, USA.
authors.forename: Domenico
authors.initials: D
authors.lastname: Coppola
authors.affiliation: Department of Surgery, University of Florida, Gainesville, FL, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Trevino
authors.affiliation: Departments of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
authors.affiliation: Departments of Gastrointestinal Oncology, Tampa, FL, USA.
authors.forename: Mokenge P
authors.initials: MP
authors.lastname: Malafa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000066673:Cell Self Renewal / Q000187:drug effects; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014810:Vitamin E; C082097:tocotrienol, delta
keywords: CSCs; EMT; VEDT; invasion; metastasis; pancreatic cancer