3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one and Neoplasm-Metastasis

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.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Melanoma, Experimental; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Pancreatic Neoplasms; Phosphofructokinase-2; Pyridines