Partial and Transient Reduction of Glycolysis by PFKFB3 Blockade Reduces Pathological Angiogenesis

Abstract

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.

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…Thus, normalization is sufficient to lead to proliferation inhibition, while healthy cells with lower glycolysis are unaffected [200]. Accordingly, targeting the 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 in hyper-sprouting blood vessels leads to a normalization of the blood vessels [201]. Not only the normalization of hyperactivated metabolic pathways leads to a therapeutic benefit, but also the reactivation of pathways that are active in healthy tissue.…”

Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication

“…An enhanced antioxidant capacity allows cancer cells to not a universal finding, and mitochondrial respiration impairment is not a fixed feature of cancer cells [41] . Although the glycolytic inhibitors targeting the Warburg effect have been investigated in various cancer types, the glycolytic inhibitors with the exception of 3-BP (a lactate analog) [18,19, , 3-BrOP (a 3-bromopyruvate derivative) [71][72][73][74] , and dichloroacetate (DCA) have demonstrated low efficacy in arresting tumor growth when used alone [99] ; these inhibitors include 2-deoxy-D-glucose (a glucose analog) [70,[100][101][102][103][104][105][106][107][108][109][110][111][112] , lonidamine (a derivative of indazole-3-carboxylic acid) [113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132] , methyl jasmonate on HK , 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one on PFK [162]…”

Metabolic control of the cell cycle

“…51 Targeting the glycolytic activator PFKFB3 reduces glycolysis and suppresses pathological angiogenesis in ischemic and inflamed tissues. 54 Unexpectedly, ECs do not rely on fatty acid oxidation for the production of ATP or redox homeostasis, but use fatty acids as a carbon source for the synthesis of DNA during cell replication, unlike multiple other cell types. 55 Additional metabolic pathways, including the pentose phosphate pathway, amino acid metabolism and others have been poorly studied in ECs in relation to (pathological) angiogenesis.…”