Sinensetin suppresses angiogenesis in liver cancer by targeting the VEGF/VEGFR2/AKT signaling pathway

Exp Ther Med. 2022 May;23(5):360. doi: 10.3892/etm.2022.11287. Epub 2022 Mar 31.

Abstract

Sinensetin (SIN) is a polymethoxy flavone primarily present in citrus fruits. This compound has demonstrated anticancer activity. However, the underlying mechanism of its action has not been fully understood. The present study investigated the impact of SIN on angiogenesis in a liver cancer model. In a murine xenograft tumor model, SIN inhibited the growth of HepG2/C3A human liver hepatoma cell-derived tumors and reduced the expression levels of platelet/endothelial cell adhesion molecule-1 and VEGF. In HepG2/C3A cells, SIN repressed VEGF expression by downregulating hypoxia-inducible factor expression. In cultured human umbilical vein endothelial cells, SIN increased apoptosis and repressed migration and tube formation. In addition, SIN decreased the phosphorylation of VEGFR2 and inhibited the AKT signaling pathway. Molecular docking demonstrated that the VEGFR2 core domain effectively combined with SIN at various important residues. Collectively, these data suggested that SIN inhibited liver cancer angiogenesis by regulating VEGF/VEGFR2/AKT signaling.

Keywords: angiogenesis; human umbilical vascular endothelial cell; liver cancer; molecular mechanism; sinensetin.

Grants and funding

Funding: The present study was financed in part by the Traditional Chinese Medicine Science and Technology Development Plan Project of Shandong Province, China (grant no. 2019-0370), the Natural Science Foundation of Shandong Province (grant nos. ZR2019BH007 and ZR2019MH128), Youth Science and Technology Innovation Team Projects of Higher Learning Institutions of Shandong Province, China (grant no. 2019KJK013) and Youth research and innovation team of Shandong University of Traditional Chinese Medicine, China (grant no. 17).