Inhibition of the VEGFR-2 tyrosine kinase domain by witd Roman chamomile extracts and phenolic compounds

Angiogenesis results from new blood vessels growing excessively (e. g. câncer). The Vascular Endothelial Growth Factor (VEGF) is secreted by the tumor cells and plays a crucial role in angiogenesis; low oxygen tension dramatically induces the expression of this major angiogenic factor that when linked to the transmembrane tyrosine kinase receptor VEGFR-2, which is present in endothelial cells, signalizes for the proliferation of these cells towards the tumor. Treatments using small molecules with anti-tyrosine kinase activity (e. g., sorafenib) can block angiogenic signalling, reduce blood tumoral irrigation, and improve chemotherapy distribution [1]. Some studies recognized phenolic compounds as chemopreventive agents, especially flavonoids. Other plant-derived anticancer drugs (e. g. Taxol) proved to be anti-angiogenic. In traditional Chinese medicine, many herbs are used in the treatment of angiogenic diseases such as chronic wounds and rheumatoid arthritis [2]. Furthermore, it has been reported that drinking of green tea could inhibit VEGF-induced angiogenesis in vivo [3]. In the present work, the anti-angiogenic activity of Roman chamomile (Chamaemelum nobile L.) extracts (methanolic extract and infusion) and main phenolic compounds (apigenin, apigenin-7-O-glucoside, caffeic acid, chlorogenic acid, luteolin, luteolin-7-O-glucoside) was evaluated through an enzymatic assay using the VEGFR-2 tyrosine kinase domain. To better understand the inhibition phosphorylation mechanism of the tyrosine kinase receptor by luteolin, apigenin and apigenin-7- 0-glucoside, docking studies were performed. The methanolic extract showed higher phosphorylation inhibition than the infusion (IC50 values of 269 and 301 μg/mL, respectively). Regarding phenolic compounds, luteolin (IC50 2.10 μM) and apigenin (IC50 4.78 μM) were the most potent in inhibiting VEGFR-2 phosphorylation, leading us to believe that these compounds are involved in the anti-angiogenic activity revealed by the methanolic extract.