Canthin-6-One Inhibits Developmental and Tumour-Associated Angiogenesis in Zebrafish

作者：Mei Fong Ng, Juliana Da Silva Viana, Pei Jean Tan, Denver D. Britto, Sy Bing Choi, Sakurako Kobayashi, Norazwana Samat, Dedrick Soon Seng Song, Satoshi Ogawa, Ishwar S. Parhar, Jonathan W. Astin, Benjamin M. Hogan, Vyomesh Patel, Kazuhide S. Okuda · 发表于：Pharmaceuticals · 年份：2024 · DOI：10.3390/ph17010108 · 被引用次数：3 · 研究领域：Zebrafish Biomedical Research Applications、Angiogenesis and VEGF in Cancer、Proteoglycans and glycosaminoglycans research

Tumour-associated angiogenesis play key roles in tumour growth and cancer metastasis. Consequently, several anti-angiogenic drugs such as sunitinib and axitinib have been approved for use as anti-cancer therapies. However, the majority of these drugs target the vascular endothelial growth factor A (VEGFA)/VEGF receptor 2 (VEGFR2) pathway and have shown mixed outcome, largely due to development of resistances and increased tumour aggressiveness. In this study, we used the zebrafish model to screen for novel anti-angiogenic molecules from a library of compounds derived from natural products. From this, we identified canthin-6-one, an indole alkaloid, which inhibited zebrafish intersegmental vessel (ISV) and sub-intestinal vessel development. Further characterisation revealed that treatment of canthin-6-one reduced ISV endothelial cell number and inhibited proliferation of human umbilical vein endothelial cells (HUVECs), suggesting that canthin-6-one inhibits endothelial cell proliferation. Of note, canthin-6-one did not inhibit VEGFA-induced phosphorylation of VEGFR2 in HUVECs and downstream phosphorylation of extracellular signal-regulated kinase (Erk) in leading ISV endothelial cells in zebrafish, suggesting that canthin-6-one inhibits angiogenesis independent of the VEGFA/VEGFR2 pathway. Importantly, we found that canthin-6-one impairs tumour-associated angiogenesis in a zebrafish B16F10 melanoma cell xenograft model and synergises with VEGFR inhibitor sunitinib malate to in...