HIV-protease inhibitors block HPV16-induced murine cervical carcinoma and promote vessel normalization in association with MMP-9 inhibition and TIMP-3 induction
| Autor: | Giovanni Barillari, Federica Maione, Yaqi Qiu, Clelia Palladino, Paolo Monini, Enrico Giraudo, Claudia Meda, Alberto Pisacane, Cecilia Sgadari, Stefania Capano, Orietta Picconi, Federico Bussolino, Anna Sapino, Barbara Ensoli, Serena Brundu |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Vascular Endothelial Growth Factor A Cancer Research Uterine Cervical Neoplasms Angiogenesis Inhibitors Antineoplastic Agents Mice Transgenic Matrix Metalloproteinase Inhibitors Cervical intraepithelial neoplasia Settore MED/04 Settore MED/05 03 medical and health sciences Mice 0302 clinical medicine Indinavir Cell Line Tumor Medicine HIV Protease Inhibitor Animals Humans Protease inhibitor (pharmacology) Tissue Inhibitor of Metalloproteinase-3 Human papillomavirus 16 Tumor hypoxia business.industry virus diseases Cancer Lopinavir HIV Protease Inhibitors medicine.disease Vascular Endothelial Growth Factor Receptor-2 Xenograft Model Antitumor Assays Disease Models Animal 030104 developmental biology Oncology Matrix Metalloproteinase 9 030220 oncology & carcinogenesis Cancer research Female business Saquinavir medicine.drug |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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