Formononetin, a novel FGFR2 inhibitor, potently inhibits angiogenesis and tumor growth in preclinical models
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Xiao Yu Wu1,*, Hao Xu2,*, Zhen Feng Wu1, Che Chen1, Jia Yun Liu1, Guan Nan Wu1, Xue Quan Yao1, Fu Kun Liu1, Gang Li3, and Liang Shen4
1 Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, China
2 Division of Gastrointestinal Surgery, Department of General Surgery, The First Afﬁliated Hospital of Nanjing Medical University, Nanjing, China
3 Department of General Surgery, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
4 Laboratory of Biotechnology and Biological Resource Utilization in Universities of Shandong, College of Life Science, Dezhou University, Dezhou, Shandong Province, China
* These authors have contributed equally to this study
Gang Li, email:
Keywords: formononetin, angiogenesis, breast cancer, FGFR2, Akt
Received: May 16, 2015 Accepted: October 21, 2015 Published: November 12, 2015
Most anti-angiogenic therapies currently being evaluated in clinical trials target vascular endothelial growth factor (VEGF) pathway, however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other potential therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here we identified formononetin as a novel agent with potential anti-angiogenic and anti-cancer activities. Formononetin demonstrated inhibition of endothelial cell proliferation, migration, and tube formation in response to basic fibroblast growth factor 2 (FGF2). In ex vivo and in vivo angiogenesis assays, formononetin suppressed FGF2-induced microvessel sprouting of rat aortic rings and angiogenesis. To understand the underlying molecular basis, we examined the effects of formononetin on different molecular components in treated endothelial cell, and found that formononetin suppressed FGF2-triggered activation of FGFR2 and protein kinase B (Akt) signaling. Moreover, formononetin directly inhibited proliferation and blocked the oncogenic signaling pathways in breast cancer cell. In vivo, using xenograft models of breast cancer, formononetin showed growth-inhibitory activity associated with inhibition of tumor angiogenesis. Moreover, formononetin enhanced the effect of VEGFR2 inhibitor sunitinib on tumor growth inhibition. Taken together, our results indicate that formononetin targets the FGFR2-mediated Akt signaling pathway, leading to the suppression of tumor growth and angiogenesis.
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