Tumor anti-angiogenic effect and mechanism of action of delta-tocotrienol

Biochem Pharmacol. 2008 Aug 1;76(3):330-9. doi: 10.1016/j.bcp.2008.05.017. Epub 2008 May 28.

Abstract

Anti-angiogenic therapy mediated by drugs and food components is an established strategy for cancer prevention. Our previous cell-culture studies identified a food-derived anti-angiogenic compound, tocotrienol (T3, an unsaturated vitamin E), as a potential angiogenic inhibitor. Among T3 isomers, delta-T3 is considered as the most potent compound. The purpose of this study was therefore to evaluate the inhibitory effect of delta-T3 on tumor angiogenesis. As growth factors (e.g., vascular endothelial growth factor and fibroblast growth factor) play critical roles in tumor angiogenesis, a conditioned medium rich in these growth factors from human colorectal adenocarcinoma cells (DLD-1-CM) was used as an angiogenic stimulus. Delta-T3 (2.5-5 microM) significantly suppressed DLD-1-CM-induced tube formation, migration, and adhesion on human umbilical vein endothelial cells. These effects were partly associated with reactive oxygen species generation by delta-T3. Western blot analysis revealed that the anti-angiogenic effect of delta-T3 is attributable to regulation of growth factor-dependent phosphatidylinositol-3 kinase (PI3K)/phosphoinositide-dependent protein kinase (PDK)/Akt signaling as well as to induction stress response in endothelial cells. Moreover, we conducted an in vivo mouse Matrigel plug angiogenesis assay, and found that delta-T3 (10-20 microg) exhibits dose-dependent inhibition of DLD-1-induced vessel formation. These results suggest that T3 has potential use as a therapeutic dietary supplement for minimizing tumor angiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Blotting, Western
  • Cell Adhesion / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Collagen
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Endothelial Cells / drug effects*
  • Endothelial Cells / enzymology
  • Humans
  • Laminin
  • Male
  • Mice
  • Mice, Nude
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Pathologic / prevention & control*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Proteoglycans
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Vitamin E / analogs & derivatives*
  • Vitamin E / pharmacology

Substances

  • Angiogenesis Inhibitors
  • Drug Combinations
  • Laminin
  • Proteoglycans
  • Reactive Oxygen Species
  • matrigel
  • Vitamin E
  • tocotrienol, delta
  • Collagen
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt