K20E, an oxidative-coupling compound of methyl caffeate, exhibits anti-angiogenic activities through down-regulations of VEGF and VEGF receptor-2

Toxicol Appl Pharmacol. 2015 Jan 15;282(2):215-26. doi: 10.1016/j.taap.2014.11.009. Epub 2014 Dec 4.

Abstract

Anti-angiogenesis is one of the most popular clinical interventions for cancer chemotherapy. A series of synthesized derivative of methyl caffeate were used to evaluate the anti-angiogenic activity and to investigate possible pharmacological mechanisms in the present study. The most potent anti-angiogenic compound was evaluated in the experiments of murine allograft tumor model and Matrigel plug assay as well as cell models in the human umbilical vascular endothelial cells (HUVECs) and the LLC1 lung cancer cells. Our results suggested that K20E suppressed the tumor growth in the allograft tumor model and exhibited anti-angiogenic activity in Matrigel plug assay. Besides, HUVEC viability was found to be significantly reduced by arresting cell cycle at G2/M phase and apoptosis. Cell migration, invasion, and tube formation of the HUVECs were also markedly suppressed by K20E treatment. K20E largely down-regulated the intracellular and secreted vascular endothelial growth factor (VEGF) in the LLC1 cancer cells. Besides, VEGF receptor-2 (VEGFR-2) and its downstream signaling cascades (AKT-mTOR and MEK1/2-ERK1/2) as well as gelatinases were all evidently reduced in the HUVECs treated with K20E. Inversely, K20E can up-regulate the expression levels of p53 and p21 proteins in the HUVECs. Based on these results, our study suggested that K20E possessed inhibiting angiogenesis through regulation of VEGF/VEGFR-2 and its downstream signaling cascades in the vascular endothelial cells (VECs).

Keywords: Angiogenesis; Human umbilical vein endothelial cells; K20E; Methyl caffeate; VEGF receptor-2; Vascular endothelial growth factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylates / pharmacology*
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Benzofurans / pharmacology*
  • Caffeic Acids / pharmacology*
  • Carcinoma, Lewis Lung / pathology
  • Cell Cycle / drug effects
  • Cell Survival / drug effects
  • Down-Regulation / drug effects
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Rats
  • Tumor Suppressor Protein p53 / genetics
  • Vascular Endothelial Growth Factor A / biosynthesis*
  • Vascular Endothelial Growth Factor Receptor-2 / biosynthesis*

Substances

  • 4-(7-acetoxy-5-(3-methoxy-3-oxoprop-1-enyl)-3-(methoxycarbonyl)-2,3-(dihydrobenzofuran-2-yl)-1,2-phenylene diacetate
  • Acrylates
  • Angiogenesis Inhibitors
  • Benzofurans
  • Caffeic Acids
  • Tumor Suppressor Protein p53
  • Vascular Endothelial Growth Factor A
  • methyl caffeate
  • Kdr protein, mouse
  • Vascular Endothelial Growth Factor Receptor-2