Abstract
Gamabufotalin (CS-6), a main active compound isolated from Chinese medicine Chansu, has been shown to strongly inhibit cancer cell growth and inflammatory response. However, its effects on angiogenesis have not been known yet. Here, we sought to determine the biological effects of CS-6 on signaling mechanisms during angiogenesis. Our present results fully demonstrate that CS-6 could significantly inhibit VEGF triggered HUVECs proliferation, migration, invasion and tubulogenesis in vitro and blocked vascularization in Matrigel plugs impregnated in C57/BL6 mice as well as reduced vessel density in human lung tumor xenograft implanted in nude mice. Computer simulations revealed that CS-6 interacted with the ATP-binding sites of VEGFR-2 using molecular docking. Furthermore, western blot analysis indicated that CS-6 inhibited VEGF-induced phosphorylation of VEGFR-2 kinase and suppressed the activity of VEGFR-2-mediated signaling cascades. Therefore, our studies demonstrated that CS-6 inhibited angiogenesis by inhibiting the activation of VEGFR-2 signaling pathways and CS-6 could be a potential candidate in angiogenesis-related disease therapy.
Highlights
Angiogenesis is a complex process which includes endothelial cells (ECs) proliferation, migration, basement membrane degeneration and new tube formation
Our present results fully demonstrate that CS-6 could significantly inhibit vascular endothelial growth factor (VEGF) triggered human umbilical vein endothelial cells (HUVECs) proliferation, migration, invasion and tubulogenesis in vitro and blocked vascularization in Matrigel plugs impregnated in C57/BL6 mice as well as reduced vessel density in human lung tumor xenograft implanted in nude mice
The number of HUVECs stimulated with VEGF for 24 h and 48 h increased about 1.25 folds and 1.9 folds, respectively. These results showed that CS-6 could inhibit VEGF-induced cell growth in a dose-dependent and time-dependent manner; we observed a greater inhibition by the CS-6 in VEGF stimulated HUVECs proliferation in comparison with absence of VEGF (Fig. 1C)
Summary
Angiogenesis is a complex process which includes endothelial cells (ECs) proliferation, migration, basement membrane degeneration and new tube formation. It is required for a variety of physiologic processes like development and reproduction. It is known that endothelial cells are normally in a highly quiescent state, and crucial to maintain vascular homeostasis. They can transform into an active proliferative state if stimulated by angiogenic factors from the tumors, grow, migrate and form new blood vessels, which offer oxygen and nutrients to the tumors. New blood vessels infiltrate tumors, supplying them with oxygen and nutrients, and offer a route for tumor metastasis. Inhibiting angiogenesis may be an effective method for inhibiting tumor growth and metastasis
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