Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma
Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma
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DOI：
10.1182/blood.v99.10.3771
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发表时间：
2002-05-15
期刊：
影响因子：
20.3
通讯作者：
Weichold, FF
中科院分区：
文献类型：
--
作者：
Pati, S;Pelser, CB;Weichold, FF
使用人类免疫缺陷病毒（HIV）蛋白酶抑制剂（如利托那韦）治疗患者可导致CD 4（+）T细胞计数增加，这与HIV-1病毒载量减少无关。两者之间缺乏相关性，导致利托那韦的其他作用可能改变HIV疾病的发病机制，我们以前的研究表明，利托那韦直接影响免疫细胞活化，增殖和凋亡的易感性。我们发现利托那韦抑制了原代内皮细胞的活化和增殖，并减少了肿瘤坏死因子α（TNF-α）、白细胞介素6（IL-6）、IL-8和血管内皮生长因子的产生，这些因子都有助于肿瘤新生血管形成和卡波西肉瘤（KS）病变的发展。利托那韦还抑制血管细胞粘附分子1、细胞间粘附分子1和E-选择素的表达，这与白细胞粘附的功能性降低相关。利托那韦可抑制由KS促进因子TNF-α、HIV-1达特蛋白或人疱疹病毒8型蛋白ORF 74诱导的核因子-κ B的转录激活。在用临床治疗中获得的浓度（3-15 μ M）的利托那韦处理后，KS衍生的细胞系在体外经历凋亡。在KS小鼠异种移植模型中，利托那韦通过KS衍生细胞抑制肿瘤形成和进展。综上所述，这些数据表明利托那韦具有与其抑制HIV蛋白酶的能力无关的抑制作用。(C)2002年，美国血液学会。
Treatment of patients with human immunodeficiency virus (HIV) protease Inhibitors such as ritonavir can result in increases in CD4(+) T-cell counts that are Independent of a reduction in HIV-1 viral load. This lack of correlation between the 2 has led to the identification of additional effects of ritonavir that potentially alter HIV disease pathogenesis, Our previous studies indicated that ritonavir directly affects immune cell activation, proliferation, and susceptibility to apoptosis. We show here that ritonavir inhibited the activation and proliferation of primary endothelial cells and decreased the production of tumor necrosis factor a (TNF-alpha interleukin 6 (IL-6), IL-8, and vascular endothelial growth factor, factors that all contribute to tumor neovascularization and to the development of Kaposi sarcoma (KS) lesions. Ritonavir also suppressed the expression of vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and E-selectin, which correlated with a functional decrease in leukocyte adhesion. Transcriptional activation of nuclear factor-kappaB, as induced by the KS-promoting factor TNF-alpha, the HIV-1 Tat protein, or the human herpesvirus 8 protein ORF74, was inhibited by ritonavir. KS-derived cell lines underwent apoptosis in vitro after treatment with ritonavir at concentrations that are obtained in clinical therapy (3-15 muM). In a KS mouse xenotransplantation model, ritonavir inhibited tumor formation and progression by KS-derived cells. Taken together, these data suggest that ritonavir has antineoplastic effects that are independent from its ability to inhibit the HIV protease. (C) 2002 by The American Society of Hematology.