HIV-protease inhibitors block HPV16-induced murine cervical carcinoma and promote vessel normalization in association with MMP-9 inhibition and TIMP-3 induction

Antiretrovirals belonging to the HIV protease inhibitor (HIV-PI) class exert inhibitory effects across several cancer types by targeting tumor cells and its microenvironment. Cervical carcinoma (CC) represents a leading cause of morbidity and mortality, particularly in women doubly infected with high-risk human papillomaviruses (HR-HPV) and the human immunodeficiency virus (HIV); of note, combined antiretroviral therapy has reduced CC onset and progression in HIV-infected women. We evaluated the effectiveness and mechanism(s) of action of HIV-PI against CC using a transgenic model of HR-HPV-induced estrogen-promoted CC (HPV16/E2) and found that mice treatment with ritonavir-boosted HIV-PI, including indinavir, saquinavir and lopinavir, blocked the growth and promoted the regression of murine CC. This was associated with inhibition of tumor angiogenesis, coupled to down-regulation of matrix metalloproteinase (MMP)-9, reduction of vascular endothelial growth factor (VEGF)/VEGF receptor-2 complex and concomitant up-regulation of tissue inhibitor of metalloproteinase-3 (TIMP-3). HIV-PI also promoted deposition of collagen IV at the epithelial and vascular basement membrane and normalization of both vessel architecture and functionality. In agreement with this, HIV-PI reduced tumor hypoxia and enhanced the delivery and anti-tumor activity of conventional chemotherapy. Remarkably, TIMP-3 expression gradually decreased during progression of human dysplastic lesions into CC. This study identifies the MMP-9/VEGF pro-angiogenic axis and its modulation by TIMP-3 as novel HIV-PI targets for the blockade of cervical intraepithelial neoplasia (CIN)/CC development and invasiveness and the normalization of tumor vessel functions. These findings may lead to new therapeutic indications of HIV-PI to treat CC and other tumors in either HIV-infected or uninfected patients.