The HIV protease inhibitor indinavir down-regulates the expression of the pro-angiogenic MT1-MMP by human endothelial cells.
Angiogenesis
; 17(4): 831-8, 2014 Oct.
Article
in En
| MEDLINE
| ID: mdl-24719186
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Gene Expression Regulation, Enzymologic
/
HIV Protease Inhibitors
/
Indinavir
/
Endothelial Cells
/
Matrix Metalloproteinase 14
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Angiogenesis
Journal subject:
HEMATOLOGIA
Year:
2014
Document type:
Article