Resveratrol Prevents EBV Transformation and Inhibits the Outgrowth of EBV-Immortalized Human B Cells

Abstract

BackgroundEpstein Barr virus-associated lymphoproliferative disease is an increasing complication in patients with immunosuppressive conditions. Although the current therapies for this disorder are effective, they are also associated with significant toxicity. In an attempt to identify newer therapeutic agents, this study investigated the effects of Resveratrol, a naturally occurring polyphenolic compound, on the EBV transformation of human B cells.Methodology/Principal FindingsThis study demonstrates that resveratrol prevents EBV transformation in human B cells. These effects are mediated by specific cytotoxic activities of resveratrol against EBV-infected B cells that are associated with the downregulation of the anti-apoptotic proteins Mcl-1 and survivin. This occurs as a consequence of the inhibition of EBV-induced NFκB and STAT-3 signaling pathways and a resveratrol-induced decrease in the expression of the oncogenic viral product LMP1 in EBV-infected B cells. In addition, resveratrol decreased the expression of miR-155 and miR-34a in EBV-infected B cells, blocked the expression of the anti-apoptotic viral gene BHRF1, and thus interrupted events that are critical for EBV transformation and the survival of EBV-transformed cells.Conclusions/SignificanceThese results suggest that resveratrol may therefore be a potentially effective therapeutic alternative for preventing EBV-associated lymphoproliferative diseases in immune compromised patients.

Dietary phytochemicals and cancer chemoprevention: a review of the clinical evidence

“…The roots of the p olygonum cuspidatum , or Japanese knotweed, contains the highest naturally occurring levels of resveratrol and has been used in traditional Japanese and Chinese medicinal treatments for dermatitis, bacterial infections and inflammation. Plants produce resveratrol in response usually to mechanical injuries, ultraviolet radiation and as a defense for viral and fungal infections [39, 40]. Resveratrol has become the most common phytoalexin currently studied in modern healthcare because of the highly publicized “French Paradox”, an observation that there is a relatively low incidence of cardiovascular disease in France despite a particularly rich saturated-fat diet from the high consumption of red wine [41].…”

“…Specifically, resveratrol can induce cancer cell apoptosis by interfering with multiple signaling pathways activated in transformed cells [40–45]. Clinical trials have also defined the safety, pharmacokinetics and metabolism as both a single synthetic agent and constituent of food at variable doses [46].…”

An update on the role of miRNA-155 in pathogenic microbial infections

“…Another link between miR-155 and EBV transformation was provided by studies on the effect of resveratrol, which blocked the expression of the anti-apoptotic viral gene BHRF1 and down-regulated the anti-apoptotic proteins Mcl-1 and survivin concomitantly with a decrease in the expression of miR-155 and miR-34a in EBV-infected B cells. Therefore, critical steps for EBV transformation and cell survival are prevented [40]. On the basis of these results it was suggested that resveratrol may be a potentially effective therapeutic alternative to prevent EBV-associated lymphoproliferative diseases in immunocompromised patients.…”

Viewing cancer pathophysiology as a lead in understanding cardiac and vascular disease mechanisms

“…In preconditioning cardioprotection, prosurvival Mcl-1 -also a Bcl-2 member -acts in a mechanism with STAT3 and NFkappa B [27]. In the process of oncogenesis this mechanism is mimicked on upregulation of Mcl-1 with NF-kappa B and STAT3 [28].…”

“…i Cancer employs the prosurvival cascade Mcl1/NF-kappa B/STAT3 [28] with the same cascade operating in cardioprotection [27].…”