Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing

In the normal quiescent vasculature, only 0.01% of endothelial cells (ECs) are proliferating. However, this proportion increases dramatically following the angiogenic switch during tumor growth or wound healing. Recent evidence suggests that this angiogenic switch is accompanied by a metabolic switch. Here, we show that proliferating ECs increasingly depend on mitochondrial oxidative phosphorylation (OxPhos) for their increased energy demand. Under growth conditions, ECs consume three times more oxygen than quiescent ECs and work close to their respiratory limit. The increased utilization of the proton motif force leads to a reduced mitochondrial membrane potential in proliferating ECs and sensitizes to mitochondrial uncoupling. The benzoquinone embelin is a weak mitochondrial uncoupler that prevents neoangiogenesis during tumor growth and wound healing by exhausting the low respiratory reserve of proliferating ECs without adversely affecting quiescent ECs. We demonstrate that this can be exploited therapeutically by attenuating tumor growth in syngenic and xenograft mouse models. This novel metabolic targeting approach might be clinically valuable in controlling pathological neoangiogenesis while sparing normal vasculature and complementing cytostatic drugs in cancer treatment. Synopsis Weak mitochondrial uncouplers prevent neoangiogenesis in vitro and in vivo by depleting cellular energy reserves in proliferating but not normal quiescent endothelial cells (ECs). New vessel formation during tumor growth requires EC proliferation and increased oxidative phosphorylation to meet the greater energy demand during angiogenesis. Weak mitochondrial uncouplers prevent neoangiogenesis by depleting cellular energy reserves in proliferating but not normal quiescent ECs. Proliferating ECs are sensitized to mitochondrial uncouplers by a reduction in membrane potential and lower respiratory reserve capacity. Genetic accumulation of mitochondrial DNA mutations in mitochondrial mutator mice highlights the link between reduced OxPhos activity and impaired angiogenic response. Weak mitochondrial uncouplers could be clinically valuable in controlling pathological neoangiogenesis while sparing normal vasculature and complementing cytostatic drugs in cancer treatment. Graphical Abstract Weak mitochondrial uncouplers prevent neoangiogenesis in vitro and in vivo by depleting cellular energy reserves in proliferating but not normal quiescent endothelial cells.