Bovine Lactoferricin Inhibits Basic Fibroblast Growth Factor- and Vascular Endothelial Growth Factor165-Induced Angiogenesis by Competing for Heparin-Like Binding Sites on Endothelial Cells

Angiogenesis is a complex process whereby new blood vessels form from pre-existing vasculature in response to proangiogenic factors such as basic fibroblast growth factor (bFGF) and the 165-kd isoform of vascular endothelial growth factor (VEGF165). Angiogenesis inhibitors show considerable potential in the treatment of cancer because angiogenesis is necessary for tumor growth beyond a few millimeters in diameter because of the tumor's need for oxygen and nutrient supply, as well as waste removal. Bovine lactoferricin (LfcinB) is a peptide fragment of iron- and heparin-binding lactoferrin obtained from cow's milk. Here we provide in vivo and in vitro evidence that LfcinB has potent antiangiogenic activity. LfcinB strongly inhibited both bFGF- and VEGF165-induced angiogenesis in Matrigel plugs implanted in C57BL/6 mice. In addition, LfcinB inhibited the in vitro proliferation and migration of human umbilical vein endothelial cells (HUVECs) in response to bFGF or VEGF165 but was not cytotoxic to HUVECs. Rather, LfcinB complexed with heparin-like structures on the HUVEC surface that are involved in the binding of bFGF and VEGF165 to their respective receptors, thereby preventing receptor-stimulated angiogenesis. These findings suggest that LfcinB may have utility as an antiangiogenic agent for the treatment of human cancers.