Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.1876
Title: ?-tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model
Authors: Siveen K.S. 
Ahn K.S.
Ong T.H.
Shanmugam M.K. 
Li F. 
Yap W.N.
Kumar A.P. 
Fong C.W.
Tergaonkar V. 
Hui K.M. 
Sethi G. 
Keywords: caspase 3
CD31 antigen
gamma tocotrienol
Ki 67 antigen
mammalian target of rapamycin
matrigel
protein kinase B
vasculotropin
vasculotropin receptor 2
alpha tocopherol
antineoplastic agent
caspase 3
chroman derivative
Ki 67 antigen
plastochromanol 8
protein kinase B
vasculotropin A
angiogenesis
animal experiment
animal model
animal tissue
antiangiogenic activity
antineoplastic activity
article
autophosphorylation
cancer inhibition
cancer tissue
capillary sprouting
cell invasion
cell viability
cellular parameters
chorioallantois
concentration response
controlled study
drug efficacy
embryo
enzyme inhibition
female
human
human cell
in vitro study
in vivo study
liver cell carcinoma
migration inhibition
mouse
nonhuman
rat
signal transduction
thoracic aorta
tube formation
tumor xenograft
umbilical vein endothelial cell
vascular ring
analogs and derivatives
animal
apoptosis
Carcinoma, Hepatocellular
cell motion
cell proliferation
cell survival
chemistry
chick embryo
drug effects
endothelium cell
Liver Neoplasms
metabolism
Neovascularization, Pathologic
SCID mouse
signal transduction
tumor cell line
vascularization
Animals
Antineoplastic Agents
Apoptosis
Carcinoma, Hepatocellular
Caspase 3
Cell Line, Tumor
Cell Movement
Cell Proliferation
Cell Survival
Chick Embryo
Chromans
Endothelial Cells
Humans
Ki-67 Antigen
Liver Neoplasms
Mice
Mice, SCID
Models, Animal
Neovascularization, Pathologic
Proto-Oncogene Proteins c-akt
Signal Transduction
Vascular Endothelial Growth Factor A
Vitamin E
Issue Date: 2014
Citation: Siveen K.S., Ahn K.S., Ong T.H., Shanmugam M.K., Li F., Yap W.N., Kumar A.P., Fong C.W., Tergaonkar V., Hui K.M., Sethi G. (2014). ?-tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model. Oncotarget 5 (7) : 1897-1911. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.1876
Abstract: Angiogenesis is one of the key hallmarks of cancer. In this study, we investigated whether ?-tocotrienol can abrogate angiogenesis-mediated tumor growth in hepatocellular carcinoma (HCC) and if so, through what molecular mechanisms. We observed that ?-tocotrienol inhibited vascular endothelial growth factor (VEGF)-induced migration, invasion, tube formation and viability of HUVECs in vitro. Moreover, ?-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, ?-tocotrienol significantly reduced the blood vessels formation. We further noticed that ?-tocotrienol blocked angiogenesis in an in vivo matrigel plug assay. Furthermore, ?-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, ?-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 ?-tocotrienol might be a promising anti-angiogenic drug with significant antitumor activity in HCC.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/174170
ISSN: 19492553
DOI: 10.18632/oncotarget.1876
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