Suppressing VEGF-A/VEGFR-2 Signaling Contributes to the Anti-Angiogenic Effects of PPE8, a Novel Naphthoquinone-Based Compound

Natural naphthoquinones and their derivatives exhibit a broad spectrum of pharmacological activities and have thus attracted much attention in modern drug discovery. However, it remains unclear whether naphthoquinones are potential drug candidates for anti-angiogenic agents. The aim of this study was to evaluate the anti-angiogenic properties of a novel naphthoquinone derivative, PPE8, and explore its underlying mechanisms. Determined by various assays including BrdU, migration, invasion, and tube formation analyses, PPE8 treatment resulted in the reduction of VEGF-A-induced proliferation, migration, and invasion, as well as tube formation in human umbilical vein endothelial cells (HUVECs). We also used an aorta ring sprouting assay, Matrigel plug assay, and immunoblotting analysis to examine PPE8's ex vivo and in vivo anti-angiogenic activities and its actions on VEGF-A signaling. It has been revealed that PPE8 inhibited VEGF-A-induced micro vessel sprouting and was capable of suppressing angiogenesis in in vivo models. In addition, PPE8 inhibited VEGF receptor (VEGFR)-2, Src, FAK, ERK1/2, or AKT phosphorylation in HUVECs exposed to VEGF-A, and it also showed significant decline in xenograft tumor growth in vivo. Taken together, these observations indicated that PPE8 may target VEGF-A-VEGFR-2 signaling to reduce angiogenesis. It also supports the role of PPE8 as a potential drug candidate for the development of therapeutic agents in the treatment of angiogenesis-related diseases including cancer.

Automated summary

This study evaluated the anti-angiogenic properties of a new naphthoquinone derivative, PPE8, and explored its mechanisms of action. The results showed that PPE8 reduced proliferation, migration, invasion, and tube formation in human umbilical vein endothelial cells (HUVECs) induced by VEGF-A. It also inhibited micro vessel sprouting and angiogenesis in vivo. Additionally, PPE8 suppressed phosphorylation of VEGFR-2, Src, FAK, ERK1/2, and AKT in HUVECs exposed to VEGF-A, and exhibited significant decline in xenograft tumor growth. These findings suggest that PPE8 may target VEGF-A-VEGFR-2 signaling to reduce angiogenesis, making it a potential drug candidate for angiogenesis-related diseases.