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Purified vitexin compound 1 inhibits growth and angiogenesis through activation of FOXO3a by inactivation of Akt in hepatocellular carcinoma.

Abstract
Vitexins, isolated from the seeds of the Chinese herb Vitex negundo, is known to exert antitumor activity in cancer xenograft models and cell lines. The aim of the current study was to examine whether the Akt/forkhead box protein O3a (FOXO3a) pathway mediates the biological effects of purified vitexin compound 1 (VB-1) in hepatocellular carcinoma (HCC) cells. The effect of VB-1 on the viability of the HCC cell lines HepG2, Hep3B, Huh-7 and the human embryonic liver cells L-02 was investigated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Growth inhibition was assessed by clonogenic assay, and cell cycle arrest was investigated using flow cytometry. Inhibition of angiogenesis was evaluated using a matrigel in vitro HUVEC tube formation assay. The effects on the Akt/FOXO3a pathway were detected by western blotting. VB-1 suppressed the proliferation of HepG2, Hep3B, Huh-7 cells, but had little effect on L-02 cells. VB-1 inhibited anchorage-dependent and -independent HepG2 cell growth in a concentration-dependent manner by induction of cell cycle arrest at G1/G0. VB-1 also reduced the secretion of vascular endothelial growth factor (VEGF), resulting in the inhibition of endothelial tube formation. Phosphorylated Akt and its downstream effector FOXO3a were downregulated in VB-1-treated HepG2 cells. Knockdown of Akt1 by small interfering RNA (siRNA) enhanced growth inhibition, and silencing FOXO3a by siRNA attenuated this action. VB-1 inhibited growth and induced cell cycle arrest at G1/G0 by regulating the Akt/FOXO3a pathway. The findings suggested that VB-1 is a potentially promising candidate for the treatment of HCC.
AuthorsJiangang Wang, Xingxing Zheng, Guangyao Zeng, Yingjun Zhou, Hong Yuan
JournalInternational journal of molecular medicine (Int J Mol Med) Vol. 33 Issue 2 Pg. 441-8 (Feb 2014) ISSN: 1791-244X [Electronic] Greece
PMID24337611 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Angiogenesis Inhibitors
  • FOXO3 protein, human
  • Forkhead Transcription Factors
  • RNA, Small Interfering
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • vitexin
  • Apigenin
  • Proto-Oncogene Proteins c-akt
Topics
  • Angiogenesis Inhibitors (pharmacology)
  • Apigenin (pharmacology)
  • Carcinoma, Hepatocellular (metabolism, pathology)
  • Cell Cycle Checkpoints (drug effects)
  • Cell Line, Tumor
  • Down-Regulation
  • Forkhead Transcription Factors (genetics, metabolism)
  • Gene Silencing
  • Hep G2 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Liver Neoplasms (metabolism)
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt (antagonists & inhibitors, genetics, metabolism)
  • RNA, Small Interfering (genetics, metabolism)
  • Signal Transduction
  • Vascular Endothelial Growth Factor A (genetics, metabolism)

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