title: Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing.
abstract: 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.
authors.affiliation: Department I for Internal Medicine, University of Cologne, Cologne, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Coutelle
authors.forename: Hue-Tran
authors.initials: HT
authors.lastname: Hornig-Do
authors.forename: Axel
authors.initials: A
authors.lastname: Witt
authors.forename: Maria
authors.initials: M
authors.lastname: Andree
authors.forename: Lars M
authors.initials: LM
authors.lastname: Schiffmann
authors.forename: Michael
authors.initials: M
authors.lastname: Piekarek
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brinkmann
authors.forename: Jens M
authors.initials: JM
authors.lastname: Seeger
authors.forename: Maxim
authors.initials: M
authors.lastname: Liwschitz
authors.forename: Satomi
authors.initials: S
authors.lastname: Miwa
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Martin
authors.initials: M
authors.lastname: Krönke
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Trifunovic
authors.forename: Sabine A
authors.initials: SA
authors.lastname: Eming
authors.forename: Rudolf J
authors.initials: RJ
authors.lastname: Wiesner
authors.forename: Ulrich T
authors.initials: UT
authors.lastname: Hacker
authors.forename: Hamid
authors.initials: H
authors.lastname: Kashkar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016227:Benzoquinones / Q000494:pharmacology*; D019069:Cell Respiration / Q000187:drug effects*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D014475:Uncoupling Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D014475:Uncoupling Agents; C010945:embelin