Simvastatin Induces Anti-Tumor Effects on Systemic CAEBV In Vitro and In Vivo

[Abstract] Background: Systemic chronic active Epstein-Barr virus infection (sCAEBV) is a rare and fatal lymphoid neoplasm characterized by sustained systemic inflammation and clonal proliferation of EBV-infected T or NK cells. Because the mechanisms responsible for the development of the disorder have not been elucidated to date, its optimal chemotherapy has not been established, and the prognosis of sCAEBV has remained very poor. We previously found and reported that simvastatin, an inhibitor of HMG-CoA reductase, inhibits prenylation of intracellular signal-mediating molecules in adult T-cell lymphoma/leukemia cells. On the basis of these findings, we hypothesized that simvastatin could also induce apoptosis in EBV-positive T or NK cells from sCAEBV. Methods: We examined two clinical samples of EBV-positive T-cell lines derived from sCAEBV, SNT8 and SNT15. The samples were obtained from six patients with sCAEBV. The in vitro effects of simvastatin on the cells were examined by XTT and Annexin V assay, and the in vivo effects of simvastatin on sCAEBV were examined in xenograft models of sCAEBV generated from NOD/Shi-scid/IL-2Rγnull mice. Results: Simvastatin suppressed proliferation and induced apoptosis in the cell lines in a dose-dependent manner. Simvastatin also suppressed proliferation and induced apoptosis of peripheral blood mononuclear cells derived from patients with sCAEBV with infected cell types of CD4 in 3 patients, CD8 in 2 patients, and CD56 in 1 patient. The presence of farnesyl pyrophosphate, one of the intermediates in the mevalonate pathway, restored the number of viable SNT8 and SNT15 cells treated with simvastatin. Furthermore, oral administration of simvastatin reduced EBV-DNA in the peripheral blood of sCAEBV xenograft models. Conclusions: Simvastatin may be an attractive reagent for sCAEBV.