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

Int J Cancer. 2009 Feb 1;124(3):622-9. doi: 10.1002/ijc.23993.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Cycle / drug effects
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Electrophoretic Mobility Shift Assay
  • Epstein-Barr Virus Infections / complications
  • Epstein-Barr Virus Infections / drug therapy*
  • HIV Protease Inhibitors / pharmacology*
  • Herpesvirus 4, Human
  • Humans
  • In Situ Hybridization, Fluorescence
  • Lymphoma, B-Cell / drug therapy*
  • Lymphoma, B-Cell / virology
  • Mice
  • NF-kappa B / drug effects*
  • NF-kappa B / metabolism
  • Polymerase Chain Reaction
  • Ritonavir / pharmacology*
  • Transcriptional Activation / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • HIV Protease Inhibitors
  • NF-kappa B
  • Ritonavir