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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-t...

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Autores principales: Patton, John T., Lustberg, Mark E., Lozanski, Gerard, Garman, Sabrina L., Towns, William H., Drohan, Callie M., Lehman, Amy, Zhang, Xiaoli, Bolon, Brad, Pan, Li, Kinghorn, A. Douglas, Grever, Michael R., Lucas, David M., Baiocchi, Robert A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413611/
https://www.ncbi.nlm.nih.gov/pubmed/25393910
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author Patton, John T.
Lustberg, Mark E.
Lozanski, Gerard
Garman, Sabrina L.
Towns, William H.
Drohan, Callie M.
Lehman, Amy
Zhang, Xiaoli
Bolon, Brad
Pan, Li
Kinghorn, A. Douglas
Grever, Michael R.
Lucas, David M.
Baiocchi, Robert A.
author_facet Patton, John T.
Lustberg, Mark E.
Lozanski, Gerard
Garman, Sabrina L.
Towns, William H.
Drohan, Callie M.
Lehman, Amy
Zhang, Xiaoli
Bolon, Brad
Pan, Li
Kinghorn, A. Douglas
Grever, Michael R.
Lucas, David M.
Baiocchi, Robert A.
author_sort Patton, John T.
collection PubMed
description 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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spelling pubmed-44136112015-05-08 The translation inhibitor silvestrol exhibits direct anti-tumor activity while preserving innate and adaptive immunity against EBV-driven lymphoproliferative disease Patton, John T. Lustberg, Mark E. Lozanski, Gerard Garman, Sabrina L. Towns, William H. Drohan, Callie M. Lehman, Amy Zhang, Xiaoli Bolon, Brad Pan, Li Kinghorn, A. Douglas Grever, Michael R. Lucas, David M. Baiocchi, Robert A. Oncotarget Research Paper 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. Impact Journals LLC 2014-06-12 /pmc/articles/PMC4413611/ /pubmed/25393910 Text en Copyright: © 2015 Patton et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Patton, John T.
Lustberg, Mark E.
Lozanski, Gerard
Garman, Sabrina L.
Towns, William H.
Drohan, Callie M.
Lehman, Amy
Zhang, Xiaoli
Bolon, Brad
Pan, Li
Kinghorn, A. Douglas
Grever, Michael R.
Lucas, David M.
Baiocchi, Robert A.
The translation inhibitor silvestrol exhibits direct anti-tumor activity while preserving innate and adaptive immunity against EBV-driven lymphoproliferative disease
title The translation inhibitor silvestrol exhibits direct anti-tumor activity while preserving innate and adaptive immunity against EBV-driven lymphoproliferative disease
title_full The translation inhibitor silvestrol exhibits direct anti-tumor activity while preserving innate and adaptive immunity against EBV-driven lymphoproliferative disease
title_fullStr The translation inhibitor silvestrol exhibits direct anti-tumor activity while preserving innate and adaptive immunity against EBV-driven lymphoproliferative disease
title_full_unstemmed The translation inhibitor silvestrol exhibits direct anti-tumor activity while preserving innate and adaptive immunity against EBV-driven lymphoproliferative disease
title_short The translation inhibitor silvestrol exhibits direct anti-tumor activity while preserving innate and adaptive immunity against EBV-driven lymphoproliferative disease
title_sort translation inhibitor silvestrol exhibits direct anti-tumor activity while preserving innate and adaptive immunity against ebv-driven lymphoproliferative disease
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413611/
https://www.ncbi.nlm.nih.gov/pubmed/25393910
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