Ritonavir or saquinavir impairs the invasion of cervical intraepithelial neoplasia cells via a reduction of MMP expression and activity.
OBJECTIVE
Treatment of human immunodeficiency virus (HIV)-infected women with the highly active antiretroviral therapy (HAART) has reduced the onset of uterine cervical intraepithelial neoplasia (CIN), and halted its progression to cervical carcinoma. We and others demonstrated that the HIV protease inhibitors (HIV-PIs) used in HAART can exert direct antitumour activities also in HIV-free preclinical or clinical models. As uterine cervical carcinoma is a leading cause of death in women independently of HIV infection, herein we assessed the impact of therapeutic concentrations of HIV-PIs including indinavir (IDV), saquinavir (SQV) or ritonavir (RTV) on cells obtained from CIN or cervical carcinoma lesions of HIV-negative women.


METHODS
HIV-PI effects were evaluated by cell invasion, growth or toxicity assays, and by RNA, protein or zymogram analyses.


RESULTS
Both SQV and RTV inhibited CIN cell invasion, and this was paralleled by a reduced expression and proteolytic activity of the matrix metalloproteinase (MMP)-2 and 9 in treated cells. SQV and RTV also reduced CIN cell growth rate, but did not affect the invasion or growth of cells derived from highly progressed cervical carcinoma.


CONCLUSIONS
As MMP-2 and MMP-9 have a key role in CIN evolution into cervical carcinoma, these results support the use of SQV or RTV for the block of CIN clinical progression in either HIV-infected or uninfected patients.
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy. barillar@uniroma2.it
Giovanni
G
Barillari
André
A
Iovane
Ilaria
I
Bacigalupo
Clelia
C
Palladino
Stefania
S
Bellino
Patrizia
P
Leone
Paolo
P
Monini
Barbara
B
Ensoli
D004847:Epithelial Cells / Q000187:drug effects*; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism; D019438:Ritonavir / Q000494:pharmacology*; D019258:Saquinavir / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy*; D002578:Uterine Cervical Dysplasia / Q000188:drug therapy*
D017320:HIV Protease Inhibitors; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D019258:Saquinavir; D019438:Ritonavir