Canthin-6-One Inhibits Developmental and Tumour-Associated Angiogenesis in Zebrafish
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 (...
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| Format: | Article |
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MDPI AG
2024-01-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/17/1/108 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Mei Fong Ng |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T10:38:22Z |
| format | Article |
| id | doaj.art-5fb5f72b7457456c83d2000c4f68f22a |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-08T10:38:22Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
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| series | Pharmaceuticals |
| spelling | doaj.art-5fb5f72b7457456c83d2000c4f68f22a2024-01-26T18:06:05ZengMDPI AGPharmaceuticals1424-82472024-01-0117110810.3390/ph17010108Canthin-6-One Inhibits Developmental and Tumour-Associated Angiogenesis in ZebrafishMei Fong Ng0Juliana Da Silva Viana1Pei Jean Tan2Denver D. Britto3Sy Bing Choi4Sakurako Kobayashi5Norazwana Samat6Dedrick Soon Seng Song7Satoshi Ogawa8Ishwar S. Parhar9Jonathan W. Astin10Benjamin M. Hogan11Vyomesh Patel12Kazuhide S. Okuda13Cancer Research Malaysia, Subang Jaya 47500, Selangor, MalaysiaOrganogenesis and Cancer Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, AustraliaCancer Research Malaysia, Subang Jaya 47500, Selangor, MalaysiaDepartment of Molecular Medicine & Pathology, School of Medical Sciences, The University of Auckland, Auckland 1010, New ZealandDepartment of Biotechnology, Faculty of Applied Sciences, UCSI University, Cheras 56000, Kuala Lumpur, MalaysiaOrganogenesis and Cancer Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, AustraliaCancer Research Malaysia, Subang Jaya 47500, Selangor, MalaysiaCancer Research Malaysia, Subang Jaya 47500, Selangor, MalaysiaBrain Research Institute, School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor, MalaysiaBrain Research Institute, School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor, MalaysiaDepartment of Molecular Medicine & Pathology, School of Medical Sciences, The University of Auckland, Auckland 1010, New ZealandOrganogenesis and Cancer Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, AustraliaCancer Research Malaysia, Subang Jaya 47500, Selangor, MalaysiaCancer Research Malaysia, Subang Jaya 47500, Selangor, MalaysiaTumour-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.https://www.mdpi.com/1424-8247/17/1/108angiogenesiszebrafishcancercanthin-6-onenatural product |
| spellingShingle | 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 Canthin-6-One Inhibits Developmental and Tumour-Associated Angiogenesis in Zebrafish Pharmaceuticals angiogenesis zebrafish cancer canthin-6-one natural product |
| title | Canthin-6-One Inhibits Developmental and Tumour-Associated Angiogenesis in Zebrafish |
| title_full | Canthin-6-One Inhibits Developmental and Tumour-Associated Angiogenesis in Zebrafish |
| title_fullStr | Canthin-6-One Inhibits Developmental and Tumour-Associated Angiogenesis in Zebrafish |
| title_full_unstemmed | Canthin-6-One Inhibits Developmental and Tumour-Associated Angiogenesis in Zebrafish |
| title_short | Canthin-6-One Inhibits Developmental and Tumour-Associated Angiogenesis in Zebrafish |
| title_sort | canthin 6 one inhibits developmental and tumour associated angiogenesis in zebrafish |
| topic | angiogenesis zebrafish cancer canthin-6-one natural product |
| url | https://www.mdpi.com/1424-8247/17/1/108 |
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