Ponatinib exerts anti-angiogenic effects in the zebrafish and human umbilical vein endothelial cells via blocking VEGFR signaling pathway
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Nana Ai1, Cheong-Meng Chong2, Weiting Chen1, Zhe Hu1, Huanxing Su2, Guokai Chen1, Queenie Wing Lei Wong1 and Wei Ge1
1Centre of Reproduction, Development and Aging (CRDA), Faculty of Health Sciences, University of Macau, Macau, China
2Institute of Chinese Medicinal Sciences (ICMS), University of Macau, Macau, China
Keywords: ponatinib; angiogenesis; eNOS; MAPK; HUVEC
Received: May 18, 2017 Accepted: December 01, 2017 Epub: January 10, 2018 Published: August 10, 2018
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.
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