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.
Keywords:
Akt; FGFR2; angiogenesis; breast cancer; formononetin.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / pharmacology*
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Aorta / drug effects
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Aorta / metabolism
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Breast Neoplasms / blood supply
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Proliferation / drug effects*
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Chick Embryo
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Chorioallantoic Membrane / blood supply
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Chorioallantoic Membrane / drug effects
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Dose-Response Relationship, Drug
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Female
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Indoles / pharmacology
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Isoflavones / pharmacology*
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MCF-7 Cells
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Male
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Mice, Inbred BALB C
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Mice, Nude
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Neovascularization, Pathologic*
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Neovascularization, Physiologic / drug effects
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrroles / pharmacology
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Rats, Sprague-Dawley
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Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors*
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Receptor, Fibroblast Growth Factor, Type 2 / metabolism
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STAT3 Transcription Factor / metabolism
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Signal Transduction / drug effects
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Sunitinib
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Time Factors
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Tumor Burden / drug effects
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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Xenograft Model Antitumor Assays
Substances
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Angiogenesis Inhibitors
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Indoles
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Isoflavones
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Protein Kinase Inhibitors
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Pyrroles
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STAT3 Transcription Factor
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STAT3 protein, human
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formononetin
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FGFR2 protein, human
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KDR protein, human
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Receptor, Fibroblast Growth Factor, Type 2
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Vascular Endothelial Growth Factor Receptor-2
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Proto-Oncogene Proteins c-akt
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Sunitinib