TY - JOUR
T1 - Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis
AU - Schoors, Sandra
AU - De Bock, Katrien
AU - Cantelmo, Anna Rita
AU - Georgiadou, Maria
AU - Ghesquière, Bart
AU - Cauwenberghs, Sandra
AU - Kuchnio, Anna
AU - Wong, Brian W.
AU - Quaegebeur, Annelies
AU - Goveia, Jermaine
AU - Bifari, Francesco
AU - Wang, Xingwu
AU - Blanco, Raquel
AU - Tembuyser, Bieke
AU - Cornelissen, Ivo
AU - Bouché, Ann
AU - Vinckier, Stefan
AU - Diaz-Moralli, Santiago
AU - Gerhardt, Holger
AU - Telang, Sucheta
AU - Cascante, Marta
AU - Chesney, Jason
AU - Dewerchin, Mieke
AU - Carmeliet, Peter
N1 - Funding Information:
We acknowledge the work of Leen Notebaert for help with the illustrations. K.D.B., A.R.C., and B.G. are Postdoctoral Fellows of the Research Foundation-Flanders (FWO); M.G. and S.S. received funding as Emmanuel Vanderschueren fellows of the Flemish Association against Cancer (VLK); and S.S. was funded by the Institution of Research and Innovation (IWT). The work of P.C. is supported by a Federal Government Belgium grant (IUAP7/03), long-term structural Methusalem funding by the Flemish Government, a Concerted Research Activities Belgium grant (GOA2006/11), grants from the FWO (G.0532.10, G.0817.11, G.0834.13, 1.5.202.10N, G.0764.10N, and 1.5.142.13N Krediet aan navorsers), the Foundation Leducq Transatlantic Network (ARTEMIS), the Foundation against Cancer, and the ERC Advanced Research Grant (EU-ERC269073). M.D. is supported by FWO grant G.0598.12. M.C. is supported by the Spanish Government and the European Union FEDER funds (SAF2011-25726), Generalitat de Catalunya-AGAUR (2009SGR1308), and the “ICREA Academia prize.” P.C. declares being named as inventor on patent applications claiming subject matter related to the results described in this paper. J.C. is coinventor of US patent #8,088,385 (PFKFB3 inhibitors for the treatment of proliferative cancer).
PY - 2014/1/7
Y1 - 2014/1/7
N2 - Strategies targeting pathological angiogenesis have focused primarily on blocking vascular endothelial growth factor (VEGF), but resistance and insufficient efficacy limit their success, mandating alternative antiangiogenic strategies. We recently provided genetic evidence that the glycolytic activator phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) promotes vessel formation but did not explore the antiangiogenic therapeutic potential of PFKFB3 blockade. Here, we show that blockade of PFKFB3 by the small molecule 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) reduced vessel sprouting in endothelial cell (EC) spheroids, zebrafish embryos, and the postnatal mouse retina by inhibiting EC proliferation and migration. 3PO also suppressed vascular hyperbranching induced by inhibition of Notch or VEGF receptor 1 (VEGFR1) and amplified the antiangiogenic effect of VEGF blockade. Although 3PO reduced glycolysis only partially and transiently in vivo, this sufficed to decrease pathological neovascularization in ocular and inflammatory models. These insights may offer therapeutic antiangiogenic opportunities.
AB - Strategies targeting pathological angiogenesis have focused primarily on blocking vascular endothelial growth factor (VEGF), but resistance and insufficient efficacy limit their success, mandating alternative antiangiogenic strategies. We recently provided genetic evidence that the glycolytic activator phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) promotes vessel formation but did not explore the antiangiogenic therapeutic potential of PFKFB3 blockade. Here, we show that blockade of PFKFB3 by the small molecule 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) reduced vessel sprouting in endothelial cell (EC) spheroids, zebrafish embryos, and the postnatal mouse retina by inhibiting EC proliferation and migration. 3PO also suppressed vascular hyperbranching induced by inhibition of Notch or VEGF receptor 1 (VEGFR1) and amplified the antiangiogenic effect of VEGF blockade. Although 3PO reduced glycolysis only partially and transiently in vivo, this sufficed to decrease pathological neovascularization in ocular and inflammatory models. These insights may offer therapeutic antiangiogenic opportunities.
UR - http://www.scopus.com/inward/record.url?scp=84891841003&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2013.11.008
DO - 10.1016/j.cmet.2013.11.008
M3 - Article
C2 - 24332967
AN - SCOPUS:84891841003
SN - 1550-4131
VL - 19
SP - 37
EP - 48
JO - Cell metabolism
JF - Cell metabolism
IS - 1
ER -