δ-Tocotrienol, a natural form of vitamin E, inhibits pancreatic cancer stem-like cells and prevents pancreatic cancer metastasis
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Kazim Husain1, Barbara A. Centeno2, Domenico Coppola2, Jose Trevino4, Said M. Sebti3 and Mokenge P. Malafa1
1Departments of Gastrointestinal Oncology, Tampa, FL, USA
2Departments of Pathology, Tampa, FL, USA
3Departments of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
4Department of Surgery, University of Florida, Gainesville, FL, USA
Mokenge P. Malafa, email: email@example.com
Keywords: VEDT, pancreatic cancer, metastasis, invasion, EMT
Received: November 16, 2016 Accepted: January 27, 2017 Published: February 28, 2017
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.
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