The translation inhibitor silvestrol exhibits direct anti-tumor activity while preserving innate and adaptive immunity against EBV-driven lymphoproliferative disease
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John T. Patton1, Mark E. Lustberg2, Gerard Lozanski3, Sabrina L. Garman1, William H. Towns1, Callie M. Drohan1, Amy Lehman4, Xiaoli Zhang4, Brad Bolon5, Li Pan6, A. Douglas Kinghorn6, Michael R. Grever1, David M. Lucas1,6,* and Robert A. Baiocchi1,*
1 Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA
2 Division of Infectious Disease, The Ohio State University, Columbus, Ohio, USA
3 Department of Pathology, The Ohio State University, Columbus, Ohio, USA
4 Center for Biostatistics, The Ohio State University, Columbus, Ohio, USA
5 Comparative Pathology and Mouse Phenotyping Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
6 Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
* These authors contributed equally to this work
Robert A. Baiocchi , email:
David M. Lucas, email:
Keywords: Lymphoproliferative disease, EBV, silvestrol, immunomodulation
Received: April 28, 2014 Accepted: June 11, 2014 Published: June 12, 2014
Treatment options for patients with Epstein-Barr Virus-driven lymphoproliferative diseases (EBV-LPD) are limited. Chemo-immunotherapeutic approaches often lead to immune suppression, risk of lethal infection and EBV reactivation, thus it is essential to identify agents that can deliver direct anti-tumor activity while preserving innate and adaptive host immune surveillance. Silvestrol possesses direct anti-tumor activity in multiple hematologic malignancies while causing minimal toxicity to normal mononuclear cells. However, the effects of silvestrol on immune function have not been described. We utilized in vitro and in vivo models of EBV-LPD to simultaneously examine the impact of silvestrol on both tumor and normal immune function. We show that silvestrol induces direct anti-tumor activity against EBV-transformed lymphoblastoid cell lines (LCL), with growth inhibition, decreased expression of the EBV oncogene latent membrane protein-1, and inhibition of the downstream AKT, STAT1 and STAT3 signaling pathways. Silvestrol promoted potent indirect anti-tumor effects by preserving expansion of innate and EBV antigen-specific adaptive immune effector subsets capable of effective clearance of LCL tumor targets in autologous co-cultures. In an animal model of spontaneous EBV-LPD, silvestrol demonstrated significant therapeutic activity dependent on the presence of CD8-positive T-cells. These findings establish a novel immune-sparing activity of silvestrol, justifying further exploration in patients with EBV-positive malignancies.
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