An HIV protease inhibitor, ritonavir targets the nuclear factor‐kappaB and inhibits the tumor growth and infiltration of EBV‐positive lymphoblastoid B cells

• Published in: International journal of cancer 2009-02, Vol.124 (3), p.622-629
• Main Authors: Dewan, Md. Zahidunnabi, Tomita, Mariko, Katano, Harutaka, Yamamoto, Norio, Ahmed, Sunjida, Yamamoto, Michiko, Sata, Tetsutaro, Mori, Naoki, Yamamoto, Naoki
• Format: Article
• Language: English
• Subjects: Animal tumors. Experimental tumors; Animals; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Cell Cycle - drug effects; Cell Movement - drug effects; Cell Proliferation - drug effects; Chemotherapy; Electrophoretic Mobility Shift Assay; Epstein-Barr virus; Epstein-Barr Virus Infections - complications; Epstein-Barr Virus Infections - drug therapy; Experimental tumors, general aspects; Herpesvirus 4, Human; HIV Protease Inhibitors - pharmacology; Human immunodeficiency virus; Humans; In Situ Hybridization, Fluorescence; LCLs; Lymphoma, B-Cell - drug therapy; Lymphoma, B-Cell - virology; Medical sciences; Mice; NF-kappa B - drug effects; NF-kappa B - metabolism; NF‐κB; NOG mice; Pharmacology. Drug treatments; Polymerase Chain Reaction; ritonavir; Ritonavir - pharmacology; Transcriptional Activation - drug effects; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.23993

Epstein‐Barr Virus (EBV)‐associated immunoblastic lymphoma occurs in immunocompromised patients such as those with AIDS or transplant recipients after primary EBV infection or reactivation of a preexisting latent EBV infection. In the present study, we evaluated the effect of ritonavir, an HIV protease inhibitor, on EBV‐positive lymphoblastoid B cells in vitro and in mice model. We found that it induced cell‐cycle arrest at G1‐phase and apoptosis through down‐regulation of cell‐cycle gene cyclin D2 and antiapoptotic gene survivin. Furthermore, ritonavir suppressed transcriptional activation of NF‐κB in these cells. Ritonavir efficiently prevented growth and infiltration of lymphoma cells in various organs of NOD/SCID/γcnull mice at the same dose used for treatment of patients with AIDS. Our results indicate that ritonavir targets NF‐κB activated in tumor cells and shows anti‐tumor effects. These data also suggest that this compound may have promise for treatment or prevention of EBV‐associated lymphoproliferative diseases that occur in immunocompromised patients. © 2008 Wiley‐Liss, Inc.