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

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, δ-T3 is considered as the most potent compound. The purpose of this study was therefore to evaluate the inhibitory effect of δ-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. δ-T3 (2.5–5 μM) 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 δ-T3. Western blot analysis revealed that the anti-angiogenic effect of δ-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 δ-T3 (10–20 μg) 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.