Abstract
Angiogenesis is a hallmark for cancer development because it is essential for cancer growth and provides the route for cancer cell migration (metastasis). Understanding the mechanism of angiogenesis and developing drugs that target the process has therefore been a major focus for research on cancer therapy. In this study, we screened 114 FDA-approved anti-cancer drugs for their effects on angiogenesis in the zebrafish. Among those with positive effects, we chose to focus on Ponatinib (AP24534; Iclusig®) for further investigation. Ponatinib is an inhibitor of the tyrosine kinase BCR-ABL in chronic myeloid leukemia (CML), and its clinical trial has been approved by FDA for the treatment of the disease. In recent clinical trials, however, some side effects have been reported for Ponatinib, mostly on blood vessel disorders, raising the possibility that this drug may influence angiogenesis. In this study, we demonstrated that Ponatinib was able to suppress the formation of intersegmental vessels (ISV) and subintestinal vessels (SIV) in the zebrafish larvae. The anti-angiogenic effect of Ponatinib was further validated by other bioassays in human umbilical vein endothelial cells (HUVECs), including cell proliferation and migration, tube formation, and wound healing. Further experiments showed that Ponatinib inhibited VEGF-induced VEGFR2 phosphorylation and its downstream signaling pathways including Akt/eNOS/NO pathway and MAPK pathways (ERK and p38MAPK). Taken together, these results suggest that inhibition of VEGF signaling at its receptor level and downstream pathways may likely be responsible for the antiangiogenic activity of Ponatinib.
Highlights
Angiogenesis is the process of new blood vessel formation and maturation from pre-existing vessels, which involves a series of cellular activities or processes including proliferation and migration of endothelial cells, vessel formation and vascular maturation [1]
These results suggest that inhibition of vascular endothelial growth factor (VEGF) signaling at its receptor level and downstream pathways may likely be responsible for the antiangiogenic activity of Ponatinib
In order to assess the in vivo effects of Ponatinib on vascular development, a transgenic zebrafish line Tg(fli1a:EGFP), which expresses EGFP in the vascular vessels, was used to monitor the formation of blood vessels, especially the intersegmental vessels (ISV) and subintestinal vessels (SIV)
Summary
Angiogenesis is the process of new blood vessel formation and maturation from pre-existing vessels, which involves a series of cellular activities or processes including proliferation and migration of endothelial cells, vessel formation and vascular maturation [1]. Angiogenesis is stimulated by various angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) family, and angiopoietins. Tumor angiogenesis is considered a main hallmark in cancer progression. Tumors and nearby normal cells in tumor microenvironment can secret proangiogenic factors to stimulate new blood vessel formation for blood supply [7]. Cancer cells can invade nearby tissues, move throughout the body, and establish new colonies via new blood vessel formation [6, 8]. Targeting angiogenesis-related mechanisms is considered an effective approach to slow down or halt the progression of cancers
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
