Since anti-angiogenic therapy has becoming a promising approach in the prevention of cancer and related diseases, the present study was aimed to examine the anti-angiogenic effect of siphonaxanthin from green alga (Codium fragile) in cell culture model systems and ex vivo approaches using human umbilical vein endothelial cells (HUVECs) and rat aortic ring, respectively. Siphonaxanthin significantly suppressed HUVEC proliferation (p<0.05) at the concentration of 2.5 μM (50% as compared with control) and above, while the effect on chemotaxis was not significant. Siphonaxanthin exhibited strong inhibitory effect on HUVEC tube formation. It suppressed the formation of tube length by 44% at the concentration of 10 μM, while no tube formation was observed at 25 μM, suggesting that it could be due to the suppression of angiogenic mediators. The ex vivo angiogenesis assay exhibited reduced microvessel outgrowth in a dose dependent manner and the reduction was significant at more than 2.5 μM. Our results imply a new insight on the novel function of siphonaxanthin in preventing angiogenesis related diseases.
Discovery of natural compounds as effective angiogenesis inhibitors has become an important approach in the prevention of cancer. We previously demonstrated the anti-angiogenic potential of two marine algal carotenoids, fucoxanthin and siphonaxanthin. In this study, we evaluated the molecular mechanisms of the anti-angiogenic activity of those two carotenoids using human umbilical vein endothelial cells. This study showed that both fucoxanthin and siphonaxanthin suppress the mRNA expression of fibroblast growth factor 2 (FGF-2) and its receptor (FGFR-1) as well as their trans-activation factor, EGR-1. But, the mRNA expression of VEGFR-2 did not show significant effect by those two carotenoids. Further, those two marine algal carotenoids down-regulate the phosphorylation of FGF-2-mediated intracellular signaling proteins such as ERK1/2 and Akt. Inhibition of FGF-2-mediated intracellular signaling proteins by those carotenoids represses the migration of endothelial cells as well as their differentiation into tube-like structures on Matrigel. These results demonstrate for the first time the possible molecular mechanism underlying the anti-angiogenic effects of fucoxanthin and siphonaxanthin and suggest that these effects are due to the down-regulation of signal transduction by FGFR-1. Our findings imply a new insight into the novel bio-functional property of marine algal carotenoids which should improve current anti-angiogenic therapies in the treatment of cancer and other pro-angiogenic diseases.
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