Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma.
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 alpha (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 microM). 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.
Pati
Shibani
S
Institute of Human Virology, University of Maryland Biotechnology Institute, Department of Microbiology and Immunology, University of Maryland, Baltimore, MD, USA.
Pelser
Colleen B
CB
Dufraine
Joseph
J
Bryant
Joseph L
JL
Reitz
Marvin S
MS
Weichold
Frank F
FF
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006133:Growth Substances / Q000096:biosynthesis; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D019438:Ritonavir / Q000494:pharmacology*; D012514:Sarcoma, Kaposi / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D016207:Cytokines; D006133:Growth Substances; D017320:HIV Protease Inhibitors; D016328:NF-kappa B; D020169:Caspases; D019438:Ritonavir