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.

中文翻译：

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HIV-蛋白酶抑制剂阻断 HPV16 诱导的小鼠宫颈癌并促进血管正常化，与 MMP-9 抑制和 TIMP-3 诱导相关

属于人类免疫缺陷病毒 (HIV) 蛋白酶抑制剂 (HIV-PI) 类的抗逆转录病毒药物通过靶向肿瘤细胞及其微环境对多种癌症类型发挥抑制作用。宫颈癌是发病率和死亡率的主要原因，特别是在双重感染高危人乳头瘤病毒 (HR-HPV) 和 HIV 的女性中；值得注意的是，联合抗逆转录病毒疗法减少了 HIV 感染女性宫颈癌的发病和进展。我们使用 HR-HPV 诱导的雌激素促进宫颈癌 (HPV16/E2) 的转基因模型评估了 HIV-PI 对宫颈癌的作用的有效性和机制，并发现用利托那韦促进的 HIV- PI，包括茚地那韦、沙奎那韦和洛匹那韦，阻断生长并促进小鼠宫颈癌的消退。这与肿瘤血管生成的抑制、基质金属蛋白酶 (MMP)-9 的下调、VEGF/VEGFR2 复合物的减少以及伴随的金属蛋白酶 3 组织抑制剂 (TIMP-3) 的上调有关。HIV-PI 还促进了胶原蛋白 IV 在上皮和血管基底膜的沉积以及血管结构和功能的正常化。与此一致的是，HIV-PI 减少了肿瘤缺氧并增强了常规化疗的递送和抗肿瘤活性。值得注意的是，在人类发育不良病变发展为宫颈癌的过程中，TIMP-3 表达逐渐降低。该研究将 MMP-9/VEGF 促血管生成轴及其通过 TIMP-3 的调节确定为新的 HIV-PI 靶标，用于阻断宫颈上皮内瘤变/宫颈癌的发展和侵袭以及肿瘤血管功能的正常化。这些发现可能导致 HIV-PI 用于治疗 HIV 感染或未感染患者的宫颈癌和其他肿瘤的新治疗适应症。