The HIV protease inhibitor indinavir down-regulates the expression of the pro-angiogenic MT1-MMP by human endothelial cells

Angiogenesis. 2014 Oct;17(4):831-8. doi: 10.1007/s10456-014-9430-9. Epub 2014 Apr 10.

Abstract

In addition to contrast human immunodeficiency virus (HIV) replication, the HIV protease inhibitors (HIV-PI) have reduced tumour incidence or clinical progression in infected patients. In this regard, we have previously shown that, independently of its anti-viral activity, the HIV-PI indinavir (IDV) directly blocks matrix metalloproteinase (MMP)-2 proteolytic activation, thus efficiently inhibiting tumour angiogenesis in vitro, in animal models, and in humans. Herein we investigated the molecular mechanism for IDV anti-angiogenic effect. We found that treatment of human primary endothelial cells with therapeutic IDV concentrations decreases the expression of membrane type (MT)1-MMP, which is the major activator of MMP-2. This occurs for both the constitutive expression of MT1-MMP and that up-regulated by angiogenic factors. In either cases, reduction of MT1-MMP levels by IDV is preceded by the inhibition of the binding of the specificity protein (Sp)1 transcription factor to the promoter region of the MT1-MMP gene in endothelial cell nuclei. As MT1-MMP is key for tumour angiogenesis, these results support the use of IDV or its derivatives in anti-cancer therapy. This is recommended by the low toxicity of the drug, and the large body of data on its pharmacokinetic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Nucleus / metabolism
  • Chromatin Immunoprecipitation
  • Endothelial Cells / metabolism*
  • Fibroblast Growth Factor 2 / metabolism
  • Gene Expression Regulation, Enzymologic*
  • HIV Protease Inhibitors / chemistry*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Indinavir / pharmacology*
  • Matrix Metalloproteinase 14 / metabolism*
  • Mice
  • Mice, Nude
  • Neovascularization, Pathologic
  • Promoter Regions, Genetic
  • Real-Time Polymerase Chain Reaction
  • Sp1 Transcription Factor / metabolism
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • HIV Protease Inhibitors
  • Sp1 Transcription Factor
  • Vascular Endothelial Growth Factor A
  • Fibroblast Growth Factor 2
  • Indinavir
  • MMP14 protein, human
  • Matrix Metalloproteinase 14