Fig. 8.

Scheme illustrating the molecular mechanisms underlying the potent inhibitory effects of clioquinol alone and its synergistic inhibitory effects with MK-2206 on angiogenesis. Clioquinol binds directly to the ATP-binding site of VEGFR2 on ECs, leading to a transient inhibition of VEGFR2 phosphorylation induced by VEGF and eventual promotion of VEGFR2 degradation via both the proteasome and lysosome systems. Consequently, the downstream ERK pathway is down-regulated. Furthermore, clioquinol increases AKT phosphorylation, while the inhibition of AKT by MK-2206 synergistically enhances the anti-angiogenic efficacy of clioquinol