Fisetin Inhibits Various Attributes of Angiogenesis in vitro and in vivo – Implications for Angioprevention
Menée sur des lignées cellulaires humaines et à l'aide d'un modèle murin, cette étude montre que la fisétine, une phytomolécule de la famille des flavonols (sous-groupe des flavonoïdes), inhibe l'expression de protéines impliquées dans l'angiogenèse
Studies have shown that fisetin, a small molecule phytochemical, has antitumor activity; however, its antiangiogenic activity has not yet been examined. Accordingly, herein, we investigated the antiangiogenic efficacy and associated mechanisms of fisetin in human umbilical vein endothelial cells (HUVEC). Fisetin (10-50 μM) strongly inhibited the regular serum plus growth supplement- and vascular endothelial growth factor (VEGF)-induced growth (up to 92%, P<0.001) and survival (up to 16%, P<0.001) of HUVEC in a dose- and time-dependant manner. Fisetin also caused cell cycle arrest at G1 (strong) and G2-M (moderate) phases together with a decrease in cyclin D1 and an increase in p53 levels. Fisetin-caused cell death was accompanied by decreased expression of survivin and an increase in cleaved levels of caspase-3 and -7, and PARP along with an increased ratio of Bax to Bcl-2. Furthermore, fisetin inhibited capillary-like tube formation on Matrigel (up to 85%, P<0.001) as well as migration (up to 66%, P<0.001) which were associated with decreased expression of eNOS and VEGF in HUVEC. It also decreased the expression of eNOS, VEGF, iNOS, MMP-2 and -9 in A549 and DU145 human cancer cells. In vivo matrigel plug assay in mice showed significant decrease in size (up to 43%, P<0.001), vascularization and hemoglobin content (up to 94%, P<0.001) in the plugs from fisetin-treated, compared to control, mice. Overall, these results suggest that fisetin inhibits various attributes of angiogenesis which might contribute to its reported antitumor effects, and therefore, fisetin warrants further investigation for its angiopreventive potential towards cancer control.
http://carcin.oxfordjournals.org/content/early/2011/12/01/carcin.bgr282.abstract