HIV Protease Inhibitors Block HPV16-Induced Murine Cervical Carcinoma and Promote Vessel Normalization in Association with MMP-9 Inhibition and TIMP-3 Induction.

Yaqi Qiu,Clelia Palladino,Serena Brundu,Federica Maione,Orietta Picconi,Barbara Ensoli,Giovanni Barillari,Paolo Monini,Claudia Meda,Anna Sapino,Federico Bussolino,Stefania Capano,Cecilia Sgadari,Enrico Giraudo,Alberto Pisacane

doi:10.1158/1535-7163.mct-20-0055

Abstract

Antiretrovirals belonging to the human immunodeficiency virus (HIV) protease inhibitor (HIV-PI) class exert inhibitory effects across several cancer types by targeting tumor cells and its microenvironment. Cervical carcinoma represents a leading cause of morbidity and mortality, particularly in women doubly infected with high-risk human papillomaviruses (HR-HPV) and HIV; of note, combined antiretroviral therapy has reduced cervical carcinoma onset and progression in HIV-infected women. We evaluated the effectiveness and mechanism(s) of action of HIV-PI against cervical carcinoma using a transgenic model of HR-HPV-induced estrogen-promoted cervical carcinoma (HPV16/E2) and found that treatment of mice with ritonavir-boosted HIV-PI, including indinavir, saquinavir, and lopinavir, blocked the growth and promoted the regression of murine cervical carcinoma. This was associated with inhibition of tumor angiogenesis, coupled to downregulation of matrix metalloproteinase (MMP)-9, reduction of VEGF/VEGFR2 complex, and concomitant upregulation 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 antitumor activity of conventional chemotherapy. Remarkably, TIMP-3 expression gradually decreased during progression of human dysplastic lesions into cervical carcinoma. This study identified the MMP-9/VEGF proangiogenic axis and its modulation by TIMP-3 as novel HIV-PI targets for the blockade of cervical intraepithelial neoplasia/cervical carcinoma development and invasiveness and the normalization of tumor vessel functions. These findings may lead to new therapeutic indications of HIV-PI to treat cervical carcinoma and other tumors in either HIV-infected or uninfected patients.

Highlights

The DNA of high-risk human papillomaviruses (HR-HPV) is detected in approximately 90% of uterine cervical carcinomas, withNote: Supplementary data for this article are available at Molecular Cancer Therapeutics Online.C
Antiretroviral treatment of HIVþ women has reduced the onset and progression of HPV-related uterine cervical lesions, and the incidence of invasive cervical carcinoma [10, 17]. Part of this effect is conceivably due to the amelioration of the immune response, previous work from us and other groups indicates that human immunodeficiency virus (HIV)-PIs exert direct antitumor and antiangiogenic effects, which are independent of their antiviral activity and may significantly contribute to tumor inhibition and regression [11, 14, 17, 18, 41, 42]
We show that therapeutic doses of HIV protease inhibitors’ (HIV-PI) are effective at inhibiting cervical carcinoma progression and tumor-associated angiogenesis, as well as at promoting lesion regression in transgenic mice through several mechanisms that may operate concurrently

Summary

Introduction

The DNA of high-risk human papillomaviruses (HR-HPV) is detected in approximately 90% of uterine cervical carcinomas, with. We show that treatment of HPV16/E2 mice with either first(indinavir and saquinavir) or second-generation [lopinavir (LPV)] HIV-PIs blocks the growth and promotes the regression of cervical carcinoma This effect was associated with inhibition of tumor angiogenesis, MMP-9 activity, and VEGF binding to VEGFR2, coupled with upregulation of tissue inhibitor of metalloproteinase-3 (TIMP-3). Because of these actions, HIV-PIs induced tumor vessel normalization and relieved tumor hypoxia in HPV16/E2 cervical carcinoma. These findings shed light on the molecular mechanisms of HIV-PIs antitumor effect and support the use of these drugs as new therapeutics against cervical carcinoma and other tumors in HIV-infected or noninfected patients

Materials and Methods

Results

Discussion

Disclosure of Potential Conflicts of Interest