Oncotarget

Research Papers:

δ-Tocotrienol, a natural form of vitamin E, inhibits pancreatic cancer stem-like cells and prevents pancreatic cancer metastasis

Kazim Husain _, Barbara A. Centeno, Domenico Coppola, Jose Trevino, Said M. Sebti and Mokenge P. Malafa

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Oncotarget. 2017; 8:31554-31567. https://doi.org/10.18632/oncotarget.15767

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Abstract

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

Correspondence to:

Mokenge P. Malafa, email: mokenge.malafa@moffitt.org

Keywords: VEDT, pancreatic cancer, metastasis, invasion, EMT

Received: November 16, 2016     Accepted: January 27, 2017     Published: February 28, 2017

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.


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