Tubacin Kills Epstein-Barr Virus (EBV)-Burkitt Lymphoma Cells by Inducing Reactive Oxygen Species and EBV Lymphoblastoid Cells by Inducing Apoptosis*

Tubacin is a small molecule inhibitor of histone deacetylase 6 and blocks aggresome activity. We found that Epstein-Barr virus (EBV)-positive Burkitt lymphoma (BL) cells were generally killed by lower doses of tubacin than EBV-transformed lymphoblastoid cells (LCLs) or EBV-negative BL cells. Tubacin induced apoptosis of LCLs, which was inhibited by pretreatment with a pancaspase inhibitor but not by butylated hydroxyanisole, which inhibits reactive oxygen species. In contrast, tubacin killed EBV-positive BL cells in a caspase-3-independent pathway that involved reactive oxygen species and was blocked by butylated hydroxyanisole. Previously, we showed that bortezomib, a proteasome inhibitor, induces apoptosis of EBV LCLs and that LCLs are killed by lower doses of bortezomib than EBV-positive BL cells. Here we found that the combination of bortezomib and tubacin acted in synergy to kill EBV-positive BL cells and LCLs. Tubacin or the combination of bortezomib and tubacin did not induce EBV lytic replication. These findings suggest that the combination of a proteasome inhibitor and an HDAC6 inhibitor may represent a useful strategy for the treatment of certain EBV-associated B cell lymphomas.

[1]  J. Cohen,et al.  Bortezomib Induces Apoptosis of Epstein-Barr Virus (EBV)-Transformed B Cells and Prolongs Survival of Mice Inoculated with EBV-Transformed B Cells , 2007, Journal of Virology.

[2]  S. Kook,et al.  Involvement of caspase activation and mitochondrial stress in trichostatin A‐induced apoptosis of Burkitt's lymphoma cell line, Akata , 2006, Journal of cellular biochemistry.

[3]  S. Kenney,et al.  Valproic acid enhances the efficacy of chemotherapy in EBV-positive tumors by increasing lytic viral gene expression. , 2006, Cancer research.

[4]  Jessica E. Bolden,et al.  Anticancer activities of histone deacetylase inhibitors , 2006, Nature Reviews Drug Discovery.

[5]  M. Pino,et al.  Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. , 2006, Cancer research.

[6]  Sudeshna Dutta,et al.  Autophagic programmed cell death by selective catalase degradation. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[7]  S. Schreiber,et al.  Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[8]  G. Perez,et al.  Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[9]  C. Long,et al.  Caspase Inhibition Protects against Reovirus-Induced Myocardial Injury In Vitro and In Vivo , 2004, Journal of Virology.

[10]  M. Caligiuri,et al.  Selective efficacy of depsipeptide in a xenograft model of Epstein-Barr virus-positive lymphoproliferative disorder. , 2004, Journal of the National Cancer Institute.

[11]  S. Grant,et al.  Synergistic Induction of Oxidative Injury and Apoptosis in Human Multiple Myeloma Cells by the Proteasome Inhibitor Bortezomib and Histone Deacetylase Inhibitors , 2004, Clinical Cancer Research.

[12]  J. Vance,et al.  The Deacetylase HDAC6 Regulates Aggresome Formation and Cell Viability in Response to Misfolded Protein Stress , 2003, Cell.

[13]  Paul Dent,et al.  The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. , 2003, Blood.

[14]  T. Caserta,et al.  Q-VD-OPh, a broad spectrum caspase inhibitor with potent antiapoptotic properties , 2003, Apoptosis.

[15]  S. Haggarty,et al.  Multidimensional chemical genetic analysis of diversity-oriented synthesis-derived deacetylase inhibitors using cell-based assays. , 2003, Chemistry & biology.

[16]  Stuart L Schreiber,et al.  Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[17]  P. Matthias,et al.  HDAC‐6 interacts with and deacetylates tubulin and microtubules in vivo , 2003, The EMBO journal.

[18]  S. Horinouchi,et al.  In vivo destabilization of dynamic microtubules by HDAC6‐mediated deacetylation , 2002, The EMBO journal.

[19]  D. Faller,et al.  Epstein-Barr virus latent membrane protein-1 induction by histone deacetylase inhibitors mediates induction of intercellular adhesion molecule-1 expression and homotypic aggregation. , 2002, Virology.

[20]  R. Kopito,et al.  Cytoplasmic dynein/dynactin mediates the assembly of aggresomes. , 2002, Cell motility and the cytoskeleton.

[21]  Xiao-Fan Wang,et al.  HDAC6 is a microtubule-associated deacetylase , 2002, Nature.

[22]  G. Wahl,et al.  c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. , 2002, Molecular cell.

[23]  J. Adams.  Proteasome inhibition: a novel approach to cancer therapy. , 2002, Trends in molecular medicine.

[24]  D. Faller,et al.  Induction of the Epstein-Barr virus thymidine kinase gene with concomitant nucleoside antivirals as a therapeutic strategy for Epstein-Barr virus-associated malignancies. , 2001, Current opinion in oncology.

[25]  Colin Adrain,et al.  Executioner Caspase-3, -6, and -7 Perform Distinct, Non-redundant Roles during the Demolition Phase of Apoptosis* , 2001, The Journal of Biological Chemistry.

[26]  J. Cohen,et al.  Epstein-Barr virus infection. , 2000, The New England journal of medicine.

[27]  R. Kopito,et al.  Aggresomes: A Cellular Response to Misfolded Proteins , 1998, The Journal of cell biology.

[28]  Eric A. Hendrickson,et al.  A Sequential Two-Step Mechanism for the Production of the Mature p17:p12 Form of Caspase-3 in Vitro * , 1997, The Journal of Biological Chemistry.

[29]  K. Takada,et al.  An Epstein-Barr virus-producer line Akata: Establishment of the cell line and analysis of viral DNA , 1991, Virus Genes.

[30]  M. Rowe,et al.  Different Epstein-Barr virus-B cell interactions in phenotypically distinct clones of a Burkitt's lymphoma cell line. , 1990, The Journal of general virology.

[31]  E. Kieff,et al.  Epstein-Barr virus latent membrane protein (LMP1) and nuclear proteins 2 and 3C are effectors of phenotypic changes in B lymphocytes: EBNA-2 and LMP1 cooperatively induce CD23 , 1990, Journal of virology.

[32]  J. Banchereau,et al.  Epstein-Barr virus (EBV) induces expression of B-cell activation markers on in vitro infection of EBV-negative B-lymphoma cells. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[33]  G. Klein,et al.  Establishment and characterization of an Epstein-Barr virus (EBC)-negative lymphoblastoid B cell line (BJA-B) from an exceptional, EBV-genome-negative African Burkitt's lymphoma. , 1975, Biomedicine / [publiee pour l'A.A.I.C.I.G.].

[34]  T. Chou,et al.  Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. , 1984, Advances in enzyme regulation.