Inhibition of CYP4A by a novel flavonoid FLA-16 prolongs survival and normalizes tumor vasculature in glioma

Cancer Lett. 2017 Aug 28:402:131-141. doi: 10.1016/j.canlet.2017.05.030. Epub 2017 Jun 7.

Abstract

Glioblastomas rapidly become refractory to anti-VEGF therapies. We previously showed that cytochrome P450 (CYP) 4A-derived 20-hydroxyeicosatetraenoic acid (20-HETE) promotes angiogenesis. Here, we tested whether a novel flavonoid (FLA-16) prolongs survival and normalizes tumor vasculature in glioma through CYP4A inhibition. FLA-16 improved survival, reduced tumor burden, and normalized vasculature, accompanied with the decreased secretion of 20-HETE, VEGF and TGF-β in tumor-associated macrophages (TAMs) and endothelial progenitor cells (EPCs) in C6 and U87 gliomas. FLA-16 attenuated vascular abnormalization induced by co-implantation of GL261 glioma cells with CYP4A10high macrophages or EPCs. Mechanistically, the conditional medium from TAMs and EPCs treated with FLA-16 enhanced the migration of pericyte cells, and decreased the proliferation and migration of endothelial cells, which were reversed by CYP4A overexpression or exogenous addition of 20-HETE, VEGF and TGF-β. Furthermore, FLA-16 prevented crosstalk between TAMs and EPCs during angiogenesis. These results suggest that CYP4A inhibition by FLA-16 prolongs survival and normalizes vasculature in glioma through decreasing production of TAMs and EPCs-derived VEGF and TGF-β. This may represent a potential therapeutic strategy to overcome resistance to anti-VEGF treatment by effects on vessels and immune cells.

Keywords: Anti-angiogenic therapy; CYP 4A; Flavonoid; Glioma; Tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Brain Neoplasms / blood supply
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Chalcones / pharmacology*
  • Culture Media, Conditioned / metabolism
  • Cytochrome P-450 CYP4A / antagonists & inhibitors*
  • Cytochrome P-450 CYP4A / metabolism
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Endothelial Progenitor Cells / drug effects*
  • Endothelial Progenitor Cells / enzymology
  • Endothelial Progenitor Cells / pathology
  • Flavonoids / pharmacology*
  • Glioma / blood supply
  • Glioma / drug therapy*
  • Glioma / enzymology
  • Glioma / pathology
  • Humans
  • Hydroxyeicosatetraenoic Acids / metabolism
  • Macrophages / drug effects*
  • Macrophages / enzymology
  • Macrophages / pathology
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neovascularization, Pathologic*
  • Paracrine Communication / drug effects
  • Pericytes / drug effects
  • Pericytes / metabolism
  • Pericytes / pathology
  • Rats, Wistar
  • Time Factors
  • Transforming Growth Factor beta / metabolism
  • Tumor Burden / drug effects
  • Tumor Microenvironment
  • Vascular Endothelial Growth Factor A / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inhibitors
  • Chalcones
  • Culture Media, Conditioned
  • Cytochrome P-450 Enzyme Inhibitors
  • FLA-16 compound
  • Flavonoids
  • Hydroxyeicosatetraenoic Acids
  • Transforming Growth Factor beta
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
  • Cytochrome P-450 CYP4A