Antiangiogenic potentials of ahpatinins obtained from a Streptomyces species

Abstract

While exploring new angiogenesis inhibitors from microbial metabolites, we recently isolated ahpatininsC, E, and G from a soil‑derived Streptomycessp. 15JA150. AhpatininsC, EandG are known to have pepsin and renin inhibitory activities; however, their antiangiogenic activities and underlying molecular mechanisms have not been fully elucidated. In the present study, the antiangiogenic properties of ahpatininsC, EandG were investigated. The results revealed that the natural compounds significantly inhibited the vascular endothelial growth factor (VEGF)‑induced proliferation, invasion, adhesion, and tube formation of human umbilical vein endothelial cells (HUVECs) without exhibiting any cytotoxicity. It was also revealed that ahpatininE effectively suppressed the neovascularization of the chorioallantoic membranes in growing chick embryos. Notably, ahpatininsC, E, and G led to the downregulation of VEGF‑induced activation of VEGF receptor2 (VEGFR2) and its downstream signaling mediators, including AKT, ERK1/2, JNK, p38, and NF‑κB, in HUVECs. Moreover, they reduced the expression of matrix metalloproteinase (MMP)‑2 and MMP‑9 in the HUVECs following stimulation with VEGF. Furthermore, ahpatininsC, E, and G reduced the tumor cell‑induced invasion and tube forming abilities of HUVECs, as well as the expression of VEGF, by suppressing hypoxia‑inducible factor‑1α (HIF‑1α) activity in U87MG glioblastoma cells. Collectively, the present findings indicated that ahpatininsC, E, and G may be used in anticancer therapy by targeting tumor angiogenesis through the inhibition of both VEGFR2 and HIF‑1α pathways.