3-O-Acetyloleanolic acid inhibits angiopoietin-1-induced angiogenesis and lymphangiogenesis via suppression of angiopoietin-1/Tie-2 signaling

Phytother Res. 2020 Feb;34(2):359-367. doi: 10.1002/ptr.6526. Epub 2019 Nov 3.

Abstract

Tumor angiogenesis and lymphangiogenesis are important processes in tumor progression and metastasis. The inhibitory effects of 3-O-acetyloleanolic acid (3AOA), a pentacyclic triterpenoid compound isolated from Vigna sinensis K., on tumor-induced angiogenesis and lymphangiogenesis in vitro and in vivo were studied. Angiopoietin-1 is an important angiogenic and lymphangiogenic factor secreted from colon carcinoma CT-26 cells under hypoxia conditions. 3AOA inhibited proliferation, migration, and tube formation of angiopoietin-1-treated human umbilical vein endothelial cells (HUVEC) and human lymphatic microvascular endothelial cells (HLMEC). 3AOA reduced angiogenesis and lymphangiogenesis in angiopoietin-1-stimulated Matrigel plugs. Also, 3AOA inhibited tumor growth and tumor-induced angiogenesis and lymphangiogenesis in an angiopoietin-1-induced CT-26 allograft colon carcinoma animal model. 3AOA inhibited activation of the angiopoietin-1 receptor Tie-2 and activation of the downstream signaling factors FAK, AKT, and ERK1/2 that are involved in the angiopoietin-1/Tie-2-signaling pathway. Thus, 3AOA has an inhibitory effect on angiogenesis and lymphangiogenesis induced by angiopoietin-1 both in vitro and in vivo, and the inhibitory effect of 3AOA is probably due to suppression of angiopoietin-1/Tie-2 signaling in HUVEC and HLMEC.

Keywords: 3-O-acetyloleanolic acid; CT-26 allograft animal model; Tie-2.; angiogenesis; angiopoietin-1; lymphangiogenesis.

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Angiopoietin-1 / metabolism*
  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Female
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Humans
  • Lymphangiogenesis / drug effects*
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms, Experimental / drug therapy
  • Neovascularization, Pathologic / drug therapy*
  • Receptor, TIE-2 / metabolism*
  • Signal Transduction / drug effects
  • Triterpenes / pharmacology*

Substances

  • ANGPT1 protein, human
  • Angiogenesis Inhibitors
  • Angiopoietin-1
  • Triterpenes
  • oleanolic acid 3-acetate
  • Receptor, TIE-2
  • TEK protein, human