Resveratrol, a Natural Antioxidant From Grapes and Red Wines, Prevents EBV-Associated Lymphoproliferation and Transformation through Inducing Apoptosis

Abstract 2543

Epstein-Barr virus (EBV) infection and reactivation is an increasing complication in immune deficient patients, particularly after allogeneic hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT). Whereas tapering of immunosuppression, donor lymphocyte infusion, and rituximab may be effective for this complication after HSCT, severe adverse events such as fatal GVHD and infections could develop thereafter. Resveratrol, a natural antioxidant compound found in grapes and red wines, possesses various biological activities including antitumor, anti-inflammatory, and antimicrobial efficacies “(Nature Reviews Drug Discovery 5, 493–506, 2006). We report here anti-EBV effects of resveratrol in eliminating EBV infected cells and preventing EBV-associated B-cell transformation. Resveratrol, at nontoxic concentrations to normal cells, effectively prevented the transformation of primary B cells derived from a panel of 16 healthy donors as well as cord blood mononuclear cells derived from 10 different donors. In addition, resveratrol induced dose-dependent apoptosis, assessed by FACS-based detection of Annexin V, in 7 different established EBV-transformed lymphoblastoid cell lines (LCLs) and in the Burkitt lymphoma EBV+ Raji and Daudi cell lines. These effects were consistently associated with the activation of caspase-8 and a 60 % down-regulation of the anti-apoptotic protein BCL-2. The addition of the caspase-8 inhibitor c-FLIPL to the cell culture vigorously inhibited the resveratrol induced apoptosis. Moreover, the resveratrol treatment decreased by 80% the EBV nuclear antigen 1 (EBNA1) expression, a critical protein required for the persistency of EBV infection. These results suggest that resveratrol may have potential roles in preventing EBV-associated lymphoproliferative diseases in immune compromised patients. Since resveratrol is a nontoxic, inexpensive and clinically available agent, it may be useful in preventing EBV- infection and reactivation after HSCT and SOT.