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Ritonavir or saquinavir impairs the invasion of cervical intraepithelial neoplasia cells via a reduction of MMP expression and activity

Barillari, Giovannia,b; Iovane, Andréa,b; Bacigalupo, Ilariaa; Palladino, Cleliaa; Bellino, Stefaniaa; Leone, Patriziaa; Monini, Paoloa; Ensoli, Barbaraa

doi: 10.1097/QAD.0b013e328351f7a5
Basic Science

Objective and design: 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.

Conclusion: 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.

aNational AIDS Center, Istituto Superiore di Sanità

bDepartment of Experimental Medicine, University ‘Tor Vergata’, Rome, Italy.

Correspondence to Giovanni Barillari, MD, PhD, Department of Experimental Medicine, University ‘Tor Vergata’, Via Montpellier 1, 00133 Rome, Italy. Tel: +39 06 72596510; fax: +39 06 72596506; e-mail:

Received 14 December, 2011

Revised 18 January, 2012

Accepted 30 January, 2012

© 2012 Lippincott Williams & Wilkins, Inc.