stilbenes and Cell-Transformation--Viral

Epstein 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.. This 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.. These results suggest that resveratrol may therefore be a potentially effective therapeutic alternative for preventing EBV-associated lymphoproliferative diseases in immune compromised patients.

Topics: Apoptosis; B-Lymphocytes; Blotting, Western; Cell Line, Transformed; Cell Transformation, Viral; Flow Cytometry; Herpesvirus 4, Human; Humans; Real-Time Polymerase Chain Reaction; Resveratrol; Stilbenes

Resveratrol, a trihydroxystilbene found in grapes and other plants, has been shown to be active in inhibiting multistage carcinogenesis. Using resveratrol as a prototype, we have synthesized a number of polyhydroxy- and polymethoxy-stilbenes and tested their anti-proliferative effect in normal and transformed human cells. Here we show that one of the resveratrol analogs, 3,4,5,4'-tetrahydroxystilbene (R-4), specifically inhibited the growth of SV40 virally transformed WI38 cells (WI38VA) at 10 microM, but had no effect on normal WI38 cells at even higher concentrations. R-4 also prominently induced apoptosis in WI38VA cells, but not in WI38 cells. RNase protection assay showed that R-4 significantly induced the expression of p53, GADD45 and Bax genes and concomitantly suppressed the expression of bcl-2 gene in WI38VA, but not in WI38 cells. A large increase in p53 DNA binding activity and the presence of p53 in the Bax promoter binding complex suggested that p53 was responsible for the Bax gene expression induced by R-4 in transformed cells. Within 4 h of treatment with R-4, the Bax to bcl-2 protein ratio in WI38 and WI38VA cells was, respectively, 0.1 and 105, a difference of three orders of magnitude. While R-4 prominently induced the p53/Bax pro-apoptotic genes, it also concomitantly suppressed the expression of Cox-2 in WI38VA cells. Taken together, our study suggests that the induction of p53 gene by R-4 in transformed cells may play a key role in the differential growth inhibition and apoptosis of transformed cells.

Topics: Apoptosis; Bacteriocins; bcl-2-Associated X Protein; Blotting, Western; Cell Division; Cell Transformation, Viral; Cells, Cultured; Cyclooxygenase 2; DNA Primers; Electrophoresis, Agar Gel; Fibroblasts; GADD45 Proteins; Gene Expression; Humans; In Situ Nick-End Labeling; Intracellular Signaling Peptides and Proteins; Isoenzymes; Lung; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Reverse Transcriptase Polymerase Chain Reaction; Stilbenes; Tumor Suppressor Protein p53