Delphinidin is a novel inhibitor of lymphangiogenesis but promotes mammary tumor growth and metastasis formation in syngeneic experimental rats

Abstract

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.

Evaluation of Antioxidant and Antiproliferative Properties of Cornus mas L. Fruit Juice

“…Recently, it was demonstrated that delphinidin blocks the proliferation of primary human blood and lymphatic endothelial cells as well as carcinoma cells in vitro in a dose-dependent manner. At higher concentrations, apoptosis of endothelial and tumor cells was induced [25].…”

“…Interestingly, in another study in vivo administration of delphinidin significantly reduced angiogenesis in the MT-450 rat syngeneic breast tumor model, although tumor growth and metastasis were promoted. The antiproliferative effect of delphinidin on cultured cells does not necessarily reflect the response of tumors to this anthocyanidin in vivo [25].…”

Analyzing the scaffold immune microenvironment using flow cytometry: practices, methods and considerations for immune analysis of biomaterials

“…[8][9][10] Most protease methods utilize combinations of different collagenases and DNase. There are several products that are commercially available including dispase, 11 liberase, [12][13][14][15][16] elastase, 17,18 and purified collagenases. 8,[19][20][21] The targets of these enzymes and reaction conditions are described in Table 1.…”

Genistein and delphinidin antagonize the genotoxic effects of the mycotoxin alternariol in human colon carcinoma cells

“…Regarding the mechanism of anti‐cancer effects, both the inhibition of receptor tyrosine kinases like the epidermal growth factor receptor (EGFR) and the catalytic inhibition of topoisomerases might contribute to this effect . However, there is also some contradiction, as the application of DEL as a free aglycon has been found to promote tumor growth and metastasis formation in rats .…”