Simvastatin induces apoptosis of Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines and delays development of EBV lymphomas

doi:10.1073/pnas.0305149101

Simvastatin induces apoptosis of Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines and delays development of EBV lymphomas

Medical Virology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

Edited by Bernard Roizman, University of Chicago, Chicago, IL, and approved February 4, 2004 (received for review August 11, 2003)

Abstract

Simvastatin and pravastatin are inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, and are used as antihypercholesterolemia drugs. Simvastatin, but not pravastatin, binds to the inserted domain of leukocyte function antigen (LFA)-1 and inhibits the function of LFA-1, including adhesion and costimulation of lymphocytes. Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) express high levels of LFA-1 on their surface and grow in tight clumps. Here we show that simvastatin (2 μM) inhibits clump formation and induces apoptosis of EBV-transformed LCLs. The apoptosis-inducing effect of simvastatin depends on binding to the inserted domain of LFA-1. Simvastatin, but not pravastatin, dissociates EBV latent membrane protein 1 from lipid rafts of LCLs, resulting in down-regulation of nuclear factor κB activity and induction of apoptosis. Analysis of multiple EBV-positive and -negative cell lines indicated that both LFA-1 and EBV latent membrane protein 1 expression were required for simvastatin's effects. Administration of simvastatin to severe combined immunodeficiency mice followed by inoculation with LCLs resulted in delayed development of EBV lymphomas and prolonged survival of animals. To our knowledge, this is the first report in which a drug that targets LFA-1 has been used to treat B cell lymphoma. These data suggest that simvastatin may have promise for treatment or prevention of EBV-associated lymphomas that occur in immunocompromised persons.

Footnotes

↵ * To whom correspondence should be addressed at: Laboratory of Clinical Infectious Diseases, National Institutes of Health, 10 Center Drive, Building 10, Room 11N228, Bethesda, MD 20892. E-mail: jcohen{at}niaid.nih.gov.
Abbreviations: EBV, Epstein-Barr virus; ICAM-1, intercellular adhesion molecule 1; I domain, inserted domain; LCL, lymphoblastoid cell line; LFA, leukocyte function antigen; LMP, latent membrane protein; PI, propidium iodide; SCID, severe combined immunodeficiency.
This paper was submitted directly (Track II) to the PNAS office.