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-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.