Repurposing of antiangiogenic agents for treatment of vascular anomalies

Blatt, Julie; Brondon, Jennifer E.; Nieman, Elizabeth L.; Phillips, Kynlon; Pandya, Arti

doi:10.1016/j.pharmthera.2023.108520

Cited by 1 publication

(1 citation statement)

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“…Further studies should aim to determine the mechanism of action of canthin-6-one and to enhance the efficacy and selectiveness of canthin-6-one through structural activity relationship studies. Apart from cancer, future studies should also investigate whether canthin-6-one can be used to treat other human diseases with excessive angiogenesis such as ocular diseases [ 49 ] and vascular anomalies [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

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

Ng,

Da Silva Viana,

Tan

et al. 2024

Pharmaceuticals

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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.

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Section: Discussionmentioning

confidence: 99%