Anti-angiogenic activity of the flavonoid precursor 4-hydroxychalcone.
Angiogenesis, the growth of new blood vessels, is necessary for cancerous tumors to keep growing and spreading. Suppression of abnormal angiogenesis may provide therapeutic strategies for the treatment of angiogenesis-dependent disorders. In the present study, we describe the in vitro and in vivo anti-angiogenic activities of the flavonoid precursor 4-hydroxychalcone (Q797). This chalcone (22μg/ml) suppressed several steps of angiogenesis, including endothelial cell proliferation, migration and tube formation without showing any signs of cytotoxicity. Moreover, we found a selective effect on activated endothelial cells, in particular with resting endothelial cells and the human epithelial tumor cell lines (HeLa, MCF-7, A549). In addition, Q797 was able to modulate both vascular endothelial growth factor (VEGF)- and basic fibroblast growth factor (FGF)- induced phosphorylation of extracellular signal-regulated kinase (ERK)-1/-2 and Akt kinase. It did not influence the nuclear translocation of p65 subunit of the nuclear factor-κB (NF-κB) when human endothelial cells were stimulated with tumor necrosis factor (TNF)-α. Taken together this indicates that the Q797-mediated inhibition of in vitro angiogenic features of endothelial cells is most likely caused by suppression of growth factor pathways. The potent inhibitory effect of Q797 on bFGF-driven neovascularization was also demonstrated in vivo using the chick chorioallantoic membrane (CAM) assay. In summary, this chalcone could serve as a new leading structure in the discovery of new potent synthetic angiogenesis inhibitors.
Department of Pharmacology, Faculty of Medicine, Pavol Jozef Safarik University, Trieda SNP 1, 04011 Kosice, Slovak Republic. lenka.varinska@upjs.sk
Lenka
L
Varinska
Michiel
M
van Wijhe
Mirella
M
Belleri
Stefania
S
Mitola
Pal
P
Perjesi
Marco
M
Presta
Pieter
P
Koolwijk
Lenka
L
Ivanova
Jan
J
Mojzis
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002642:Chick Embryo; D015195:Drug Design; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005337:Fibrin / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D047188:Chalcones; C451019:4-hydroxychalcone; D005337:Fibrin