Canthin-6-One Inhibits Developmental and Tumour-Associated Angiogenesis in Zebrafish
- Author(s)
- Ng, MF; Da Silva Viana, J; Tan, PJ; Britto, DD; Choi, SB; Kobayashi, S; Samat, N; Song, DSS; Ogawa, S; Parhar, IS; Astin, JW; Hogan, BM; Patel, V; Okuda, KS;
- Details
- Publication Year 2024-01-12,Volume 17,Issue #1,Page 108
- Journal Title
- Pharmaceuticals
- Publication Type
- Research article
- Abstract
- 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 inhibit developmental angiogenesis. In summary, we showed that canthin-6-one exhibits anti-angiogenic properties in both developmental and pathological contexts in zebrafish, independent of the VEGFA/VEGFR2 pathway and demonstrate that canthin-6-one may hold value for further development as a novel anti-angiogenic drug.
- Publisher
- MDPI
- Keywords
- angiogenesis; cancer; canthin-6-one; natural product; zebrafish
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.3390/ph17010108
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- Refer to copyright notice on published article.
Creation Date: 2024-02-20 12:41:06
Last Modified: 2024-02-20 12:45:33