Cyclic chalcone analogue KRP6 as a potent modulator of cell proliferation: an in vitro study in HUVECs

Abstract

In the present investigation a novel series of chalcone analogues were synthesized and evaluated for their anti-proliferative activity in human umbilical vein endothelial cells (HUVECs). Among 14 tested compounds, chalcone analogue (E)-3-(2'-methoxybenzylidene)-4-chromanone (KRP6) exhibited the most potent activity with IC50 19 μM. Moreover, HUVECs exhibited divergent, even opposing concentration-dependent responses to KRP6. This compound was the most potent inhibitor of cell proliferation and extracellular matrix formation (fibronectin and type IV collagen) at higher concentrations (20-50 μM). In contrast, KRP6 stimulated the compensatory increase in proliferative activity including extracellular matrix formation at low concentrations (1, 10 μM). KRP6 concentration-dependently modulated phosphorylation of Akt and mitogen-activated protein kinases such as extracellular signal-regulated kinase-1/-2 and p38 kinase, suggesting that these pathways play a role in the effect mediated by this compound. In addition, we found a selective effect on activated endothelial cells, in particular with resting endothelial cells. In conclusion, KRP6 is a potent modulator of selected steps of the angiogenic process in vitro. Accordingly, further in vivo research should be performed to facilitate its use in clinical practice.

Antiangiogenic Effect of Flavonoids and Chalcones: An Update

“…Depending on the concentration it modulated phosphorylation of AKT and ERK1/2 and p38MAPK, suggesting that these pathways play a role in the effect mediated by this compound. Similar to 4-hydroxychalcone, it expressed selective effects on activated endothelial cells [ 148 ].…”

Soy and Breast Cancer: Focus on Angiogenesis

“…Tumor angiogenesis can be inhibited by blocking some of these steps. Several papers have been published referring on the modulatory effect of flavonoids on angiogenesis [71,72,73,74,75,76,77,78]. Soy isoflavonoids also exhibit anti-angiogenic activities, but the precise mechanism of inhibition remains unclear.…”

Synthesis and Biological Evaluation of Novel Homoisoflavonoids for Retinal Neovascularization

“…One compound, ( E )-3-(3-hydroxy-4-methoxybenzylidene)-6-methyl-4-chromanone was shown to have submicromolar antiangiogenic effects in vitro and efficacy in a laser-induced choroidal neovascularization model, 11 while a related compound ( E )-3-(-2methoxybenzylidene)-4-chromanone was shown to have antiproliferative effects on human umbilical vein endothelial cells (HUVECs). 12 Of natural-source homoisoflavanones, methylophiopogonanone B blocked HUVEC angiogenesis and the hypoxic response in vitro, 13 while very recently methylophiopogonanone A was shown to block brain endothelial cell activation. 14 In addition, considerable work has documented antiangiogenic effects of the related chalcones, flavones and flavanones.…”