γ-tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model
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Kodappully Sivaraman Siveen1,*, Kwang Seok Ahn2,*, Tina H. Ong3, Muthu K. Shanmugam1, Feng Li1, Wei Ney Yap1,4, Alan Prem Kumar1,4,5,6, Chee Wai Fong7, Vinay Tergaonkar8, Kam M Hui3,8,9,10 and Gautam Sethi1,4
1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
2 College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea
3 Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore
4 Cancer Science Institute of Singapore, Centre for Translational Medicine, 14 Medical Drive, #11-01M, Singapore
5 School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Western Australia 6009, Australia
6 Department of Biological Sciences, University of North Texas, Denton, Texas, 76203, USA
7 Davos Life Science Pte Ltd, 3 Biopolis Drive; #04-19 Synapse, Singapore
8 Institute of Molecular and Cell Biology, A*STAR, Biopolis Drive Proteos, Singapore
9 Cancer and Stem Cell Biology Program, Duke–National University of Singapore Graduate Medical School, Singapore
10 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
* contributed equally to this work
Gautam Sethi, email:
Kam M Hui, email:
Keywords: γ-tocotrienol, HCC, angiogenesis, AKT/mTOR, orthotopic model.
Received: January 6, 2014 Accepted:March 30, 2014 Published: March 31, 2014
Angiogenesis is one of the key hallmarks of cancer. In this study, we investigated whether γ-tocotrienol can abrogate angiogenesis-mediated tumor growth in hepatocellular carcinoma (HCC) and if so, through what molecular mechanisms. We observed that γ-tocotrienol inhibited vascular endothelial growth factor (VEGF)-induced migration, invasion, tube formation and viability of HUVECs in vitro. Moreover, γ-tocotrienol reduced the number of capillary sprouts from matrigel embedded rat thoracic aortic ring in a dose-dependent manner. Also, in chick chorioallantoic membrane assay, γ-tocotrienol significantly reduced the blood vessels formation. We further noticed that γ-tocotrienol blocked angiogenesis in an in vivo matrigel plug assay. Furthermore, γ-tocotrienol inhibited VEGF-induced autophosphorylation of VEGFR2 in HUVECs and also suppressed the constitutive activation of AKT/mammalian target of rapamycin (mTOR) signal transduction cascades in HUVECs as well as in HCC cells. Interestingly, γ-tocotrienol was also found to significantly reduce the tumor growth in an orthotopic HCC mouse model and inhibit tumor-induced angiogenesis in HCC patient xenografts through the suppression of various biomarkers of proliferation and angiogenesis. Taken together, our findings strongly suggest that γ-tocotrienol might be a promising anti-angiogenic drug with significant antitumor activity in HCC.
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