Tumor vessel disintegration by maximum tolerable PFKFB3 blockade

Angiogenesis. 2017 Nov;20(4):599-613. doi: 10.1007/s10456-017-9573-6. Epub 2017 Sep 5.


Blockade of the glycolytic activator PFKFB3 in cancer cells (using a maximum tolerable dose of 70 mg/kg of the PFKFB3 blocker 3PO) inhibits tumor growth in preclinical models and is currently being tested as a novel anticancer treatment in phase I clinical trials. However, a detailed preclinical analysis of the effects of such maximum tolerable dose of a PFKFB3 blocker on the tumor vasculature is lacking, even though tumor endothelial cells are hyper-glycolytic. We report here that a high dose of 3PO (70 mg/kg), which inhibits cancer cell proliferation and reduces primary tumor growth, causes tumor vessel disintegration, suppresses endothelial cell growth for protracted periods, (model-dependently) aggravates tumor hypoxia, and compromises vascular barrier integrity, thereby rendering tumor vessels more leaky and facilitating cancer cell intravasation and dissemination. These findings contrast to the effects of a low dose of 3PO (25 mg/kg), which induces tumor vessel normalization, characterized by vascular barrier tightening and maturation, but reduces cancer cell intravasation and metastasis. Our findings highlight the importance of adequately dosing a glycolytic inhibitor for anticancer treatment.

Keywords: Angiogenesis; Anti-angiogenic therapy; Glycolysis; Metabolism; PFKFB3.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Melanoma, Experimental / blood supply
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / ultrastructure
  • Mice, Inbred C57BL
  • Neoplasm Metastasis
  • Neoplasms / blood supply*
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / pathology
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / pathology
  • Phosphofructokinase-2 / antagonists & inhibitors*
  • Phosphofructokinase-2 / metabolism
  • Pyridines / pharmacology


  • 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one
  • Pyridines
  • Phosphofructokinase-2