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Activated endothelial cells play a crucial role in the formation of new blood vessels, a process known as angiogenesis, which can underlie the development of several diseases. Different antiangiogenic therapies aimed against vascular endothelial growth factor (VEGF), the dominant pro-angiogenic cytokine, have been developed. Because the treatment is limited in its efficiency and has side effects, new approaches are currently being evaluated. One of them is aimed at blocking glycolysis, the dominant energetic pathway of activated endothelial cells during vessel sprouting. In the present study we investigated the efficiency of a combined strategy to inhibit glycolysis and block VEGF action on proliferation and migration in human endothelial cells. Human endothelial cells (HUVECs) were treated with different doses of the glycolysis inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) in combination with the multikinase inhibitor sunitinib l-malate. Our results show that HUVECs with reduced glycolytic activity are more sensitive to co-administered sunitinib. Analysis of post-receptor pathways controlling proliferation and migration of HUVECs showed suppression of phosphorylated PI3K/Akt and ERK1/2 after exposure to sunitinib but not to 3PO in 10 µM concentration. Our results suggest that simultaneous inhibition of energy metabolism and blocking of pro-angiogenic growth factor signalling pathways can be a promising strategy to inhibit the pathological form of angiogenesis.

Synergic effects of inhibition of glycolysis and multikinase receptor signalling on proliferation and migration of endothelial cells