An HIV protease inhibitor, ritonavir targets the nuclear factor-kappaB and inhibits the tumor growth and infiltration of EBV-positive lymphoblastoid B cells.
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-kappaB in these cells. Ritonavir efficiently prevented growth and infiltration of lymphoma cells in various organs of NOD/SCID/gammacnull mice at the same dose used for treatment of patients with AIDS. Our results indicate that ritonavir targets NF-kappaB 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.
Dewan
Md Zahidunnabi
MZ
Department of Molecular Virology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Tomita
Mariko
M
Katano
Harutaka
H
Yamamoto
Norio
N
Ahmed
Sunjida
S
Yamamoto
Michiko
M
Sata
Tetsutaro
T
Mori
Naoki
N
Yamamoto
Naoki
N
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D004854:Herpesvirus 4, Human; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000821:virology; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D019438:Ritonavir / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D017320:HIV Protease Inhibitors; D016328:NF-kappa B; D019438:Ritonavir