Antiangiogenic potentials of ahpatinins obtained from a Streptomyces species

Han,Jang   Mi; Jang,Jun‑Pil; Jang,Jae‑Hyuk; Ahn,Jong   Seog; Jung,Hye   Jin

doi:10.3892/or.2019.7446

Antiangiogenic potentials of ahpatinins obtained from a Streptomyces species

Authors:
- Jang Mi Han
- Jun‑Pil Jang
- Jae‑Hyuk Jang
- Jong Seog Ahn
- Hye Jin Jung
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Affiliations: Department of Life Science and Biochemical Engineering, Sun Moon University, Asan, South Chungcheong 31460, Republic of Korea, Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, North Chungcheong 28116, Republic of Korea, Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, North Chungcheong 28116, Republic of Korea
Published online on: December 24, 2019 https://doi.org/10.3892/or.2019.7446
Pages: 625-634

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Abstract

While exploring new angiogenesis inhibitors from microbial metabolites, we recently isolated ahpatinins C, E, and G from a soil‑derived Streptomyces sp. 15JA150. Ahpatinins C, E and G 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 ahpatinins C, E and G 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 ahpatinin E effectively suppressed the neovascularization of the chorioallantoic membranes in growing chick embryos. Notably, ahpatinins C, E, and G led to the downregulation of VEGF‑induced activation of VEGF receptor 2 (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, ahpatinins C, 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 ahpatinins C, E, and G may be used in anticancer therapy by targeting tumor angiogenesis through the inhibition of both VEGFR2 and HIF‑1α pathways.

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