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Journal of Virology, September 2007, p. 10029-10036, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.02241-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Bortezomib Induces Apoptosis of Epstein-Barr Virus (EBV)-Transformed B Cells and Prolongs Survival of Mice Inoculated with EBV-Transformed B Cells{triangledown}

Ping Zou,{dagger},{ddagger} Junichi Kawada,{dagger} Lesley Pesnicak, and Jeffrey I. Cohen*

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

Received 12 October 2006/ Accepted 5 July 2007

Bortezomib, an inhibitor of the 26S proteasome, is currently approved for treatment of multiple myeloma and is being studied for therapy of non-Hodgkin's lymphoma. We found that Epstein-Barr virus (EBV)-positive B cells with type III latency were more susceptible to killing by bortezomib than those with type I latency. Bortezomib induced apoptosis of EBV lymphoblastoid cell lines (LCLs) by inducing cleavage of caspases 8 and 9; apoptosis was inhibited by pretreatment with a pan-caspase inhibitor. Bortezomib reduced the levels of the p50 and p65 components of the canonical NF-{kappa}B pathway and reduced the level of p52 in the noncanonical NF-{kappa}B pathway, which is induced by EBV LMP1. Bortezomib inhibited expression of cIAP-1, cIAP-2, and XIAP, which are regulated by NF-{kappa}B and function as inhibitors of apoptosis. Bortezomib did not inhibit expression of several other antiapoptotic proteins, including Bcl-2 and Bcl-XL. Finally, bortezomib significantly prolonged the survival of severe combined immunodeficiency mice inoculated with LCLs. These findings suggest that bortezomib may represent a novel strategy for the treatment of certain EBV-associated lymphomas.

* Corresponding author. Mailing address: Laboratory of Clinical Infectious Diseases, National Institutes of Health, 10 Center Drive, Building 10, Room 11N234, Bethesda, MD 20892. Phone: (301) 496-5265. Fax: (301) 496-7383. E-mail: jcohen{at}niaid.nih.gov

{triangledown} Published ahead of print on 11 July 2007.

{dagger} P.Z. and J.K. contributed equally to this paper.

{ddagger} Present address: Department of Microbiology, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.

Journal of Virology, September 2007, p. 10029-10036, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.02241-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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