Formononetin, a novel FGFR2 inhibitor, potently inhibits angiogenesis and tumor growth in preclinical models.

Xiao Yu Wu,Zhen Feng Wu,Hao Xu,Guan Nan Wu,Fu Kun Liu,Gang Li,Che Chen,Xue Quan Yao,Jia Yun Liu,Liang Shen

doi:10.18632/oncotarget.6310

Abstract

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.

Highlights

Tumor angiogenesis is essential for the development and progression of malignant tumors [1]
On the basis of the potent in vitro and in vivo antiangiogenic and anti-cancer growth properties elicited by formononetin, we examined if formononetin could enhance the anti-cancer growth efficacy of sunitinib, a Vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor
Among the numerous factors involved in angiogenesis, the role of vascular endothelial growth factor (VEGF) and VEGFR2 is well established, but other angiogenic factors switch on during cancer progression and induce resistance to VEGFR inhibitors monotherapy [2]

Summary

Introduction

Tumor angiogenesis is essential for the development and progression of malignant tumors [1]. Recent studies have identified FGF2 as a direct activator of phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K)-protein kinase B (Akt), which are key stimuli known to initiate endothelial cell migration, invasion and differentiation. Akt regulates multiple cellular processes including tumor angiogenesis, cell cycle progression, cell growth, cell migration, and cell metabolism [7]. Fbroblast growth factor receptor 2 (FGFR2) activation after FGF2 binding causes phosphorylation of Akt signaling resulting in increased activation of signal transducer and activator of transcription 3 (STAT3), c-Jun and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 [8]. The activation of STAT3 results in expression of many target genes including matrix metalloproteinases (MMPs), cyclooxygenase-2 (COX-2) and angiopoietin-2 (Ang-2) which are required for tumor cell migration, angiogenesis as well as metastasis [9]

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Results

Conclusion