A natural small molecule harmine inhibits angiogenesis and suppresses tumour growth through activation of p53 in endothelial cells

PLoS One. 2012;7(12):e52162. doi: 10.1371/journal.pone.0052162. Epub 2012 Dec 27.

Abstract

Activation of p53 effectively inhibits tumor angiogenesis that is necessary for tumor growth and metastasis. Reactivation of the p53 by small molecules has emerged as a promising new strategy for cancer therapy. Several classes of small-molecules that activate the p53 pathway have been discovered using various approaches. Here, we identified harmine (β-carboline alkaloid) as a novel activator of p53 signaling involved in inhibition of angiogenesis and tumor growth. Harmine induced p53 phosphorylation and disrupted the p53-MDM2 interaction. Harmine also prevented p53 degradation in the presence of cycloheximide and activated nuclear accumulation of p53 followed by increasing its transcriptional activity in endothelial cells. Moreover, harmine not only induced endothelial cell cycle arrest and apoptosis, but also suppressed endothelial cell migration and tube formation as well as induction of neovascularity in a mouse corneal micropocket assay. Finally, harmine inhibited tumor growth by reducing tumor angiogenesis, as demonstrated by a xenograft tumor model. Our results suggested a novel mechanism and bioactivity of harmine, which inhibited tumor growth by activating the p53 signaling pathway and blocking angiogenesis in endothelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Aorta / metabolism
  • Aorta / pathology
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Cycle / drug effects
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Comet Assay
  • Fluorescent Antibody Technique
  • Hallucinogens / pharmacology
  • Harmine / pharmacology*
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / drug effects*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Immunoprecipitation
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / pathology
  • Lung Neoplasms / prevention & control*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neovascularization, Pathologic / drug therapy*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Rats
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inhibitors
  • Hallucinogens
  • RNA, Messenger
  • RNA, Small Interfering
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Harmine
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2

Grants and funding

This study was partially sponsored by the Major State Basic Research Development Program of China (2012CB910400) (http://www.most.gov.cn), (2009CB918402) (http://www.973.gov.cn), National Natural Science Foundation of China (30930055, 30971523 and 81071807) (http://www.nsfc.gov.cn) and the Science and Technology Commission of Shanghai Municipality (11DZ2260300) (http://www.stcsm.gov.cn). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.