Y-tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model.
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.
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Kodappully Sivaraman
KS
Siveen
Kwang Seok
KS
Ahn
Tina H
TH
Ong
Muthu K
MK
Shanmugam
Feng
F
Li
Wei Ney
WN
Yap
Alan Prem
AP
Kumar
Chee Wai
CW
Fong
Vinay
V
Tergaonkar
Kam M
KM
Hui
Gautam
G
Sethi
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000737:chemistry / Q000188:drug therapy*; D053148:Caspase 3 / Q000032:analysis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D002839:Chromans / Q000494:pharmacology*; D042783:Endothelial Cells; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008113:Liver Neoplasms / Q000098:blood supply / Q000737:chemistry / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D023421:Models, Animal; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D002839:Chromans; D019394:Ki-67 Antigen; D042461:Vascular Endothelial Growth Factor A; D014810:Vitamin E; C013649:plastochromanol 8; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3