Murrangatin suppresses angiogenesis induced by tumor cell-derived media and inhibits AKT activation in zebrafish and endothelial cells

Drug Des Devel Ther. 2018 Sep 24:12:3107-3115. doi: 10.2147/DDDT.S145956. eCollection 2018.

Abstract

Introduction: Lung cancer is a major cancer type and a leading cause of cancer-related death. Angiogenesis plays a crucial role in lung cancer pathogenesis and its inhibition is beneficial to patients.

Materials and methods: Murrangatin, a natural product, can inhibit the proliferation of lung cancer cells, so herein we investigated its anti-angiogenic effects in transgenic zebrafish TG (fli1: EGFP) and in lung cancer cell-induced angiogenesis in human umbilical vein endothelial cells.

Results: We found that murrangatin strongly inhibited the growth of subintestinal vessels in zebrafish embryos and tumor conditioned media-induced angiogenic phenotypes including cell proliferation, cell invasion, cell migration, and tube formation. Additionally, murrangatin greatly attenuated conditioned medium-induced AKT phosphorylation, but not extracellular signal-regulated kinase 1/2 phosphorylation.

Discussion and conclusion: These findings indicate that murrangatin can inhibit tumor-induced angiogensis, at least in part through the regulation of AKT signaling pathways. Murrangatin may, therefore, be a potential candidate for the development of new anti-lung-cancer drugs.

Keywords: AKT; HUVECs; anti-angiogenesis; conditioned medium; murrangatin; zebrafish.

MeSH terms

  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / isolation & purification
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Biological Products / chemistry
  • Biological Products / isolation & purification
  • Biological Products / pharmacology
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Coumarins / chemistry
  • Coumarins / isolation & purification
  • Coumarins / pharmacology*
  • Culture Media, Conditioned / chemistry
  • Culture Media, Conditioned / pharmacology
  • Drug Screening Assays, Antitumor
  • Human Umbilical Vein Endothelial Cells / drug effects*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Molecular Conformation
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / isolation & purification
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • Zebrafish / embryology

Substances

  • Angiogenesis Inhibitors
  • Biological Products
  • Coumarins
  • Culture Media, Conditioned
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt