We have recently demonstrated that the
anthocyanidin delphinidin (DEL), one of the most abundant dietary
flavonoids, inhibits activation of ErbB and
vascular endothelial growth factor receptor family members. These receptors play crucial roles in the context of
tumor progression and the outgrowth of blood and lymphatic vessels. Here, we have developed an improved chemical synthesis for DEL in order to study the effects of the aglycon and its degradation product
gallic acid (GA) on endothelial and
tumor cells in vitro and in vivo. We found that DEL blocked the proliferation in vitro of primary human blood and lymphatic endothelial cells as well as human HT29 colon and rat MT-450 mammary
carcinoma cells in a dose-dependent manner. In contrast, its degradation product GA had little effect. At higher concentrations, DEL induced apoptosis of endothelial and
tumor cells. Furthermore, DEL potently blocked the outgrowth of lymphatic capillaries in ex vivo lymphangiogenesis assays. In the MT-450 rat syngeneic
breast tumor model, it also significantly reduced angiogenesis and
tumor-induced lymphangiogenesis when administered in vivo. These data reveal DEL to be a novel antilymphangiogenesis
reagent. Surprisingly, however, the application of DEL unexpectedly promoted
tumor growth and
metastasis in the MT-450
tumor model, suggesting that the antiproliferative effect of DEL on cultured cells does not necessarily reflect the response of
tumors to this
anthocyanidin in vivo. Furthermore, while DEL may have utility as a
cancer chemopreventative agent, its ability to promote
tumor growth once a
neoplasm develops also needs to be taken into consideration.