The translation inhibitor silvestrol exhibits direct anti-tumor activity while preserving innate and adaptive immunity against EBV-driven lymphoproliferative disease.
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.
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
John T
JT
Patton
Division of Infectious Disease, The Ohio State University, Columbus, Ohio, USA.
Mark E
ME
Lustberg
Department of Pathology, The Ohio State University, Columbus, Ohio, USA.
Gerard
G
Lozanski
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
Sabrina L
SL
Garman
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
William H
WH
Towns
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
Callie M
CM
Drohan
Center for Biostatistics, The Ohio State University, Columbus, Ohio, USA.
Amy
A
Lehman
Center for Biostatistics, The Ohio State University, Columbus, Ohio, USA.
Xiaoli
X
Zhang
Comparative Pathology and Mouse Phenotyping Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
Brad
B
Bolon
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
Li
L
Pan
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
A Douglas
AD
Kinghorn
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
Michael R
MR
Grever
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA.|Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
David M
DM
Lucas
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
Robert A
RA
Baiocchi
D056704:Adaptive Immunity / Q000187:drug effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D020031:Epstein-Barr Virus Infections / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008232:Lymphoproliferative Disorders / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016513:Mice, SCID; D014176:Protein Biosynthesis / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014315:Triterpenes / Q000494:pharmacology*; D014763:Viral Matrix Proteins / Q000378:metabolism; D001572:Benzofurans
D000970:Antineoplastic Agents; D051057:Proto-Oncogene Proteins c-akt; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D014315:Triterpenes; D014763:Viral Matrix Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C489897:silvestrol; D001572:Benzofurans