title: Tubacin kills Epstein-Barr virus (EBV)-Burkitt lymphoma cells by inducing reactive oxygen species and EBV lymphoblastoid cells by inducing apoptosis.
abstract: 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.
authors.affiliation: From the Medical Virology Section, Laboratory of Clinical Infectious Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892-1888.
authors.forename: Junichi
authors.initials: J
authors.lastname: Kawada
authors.affiliation: From the Medical Virology Section, Laboratory of Clinical Infectious Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892-1888.
authors.forename: Ping
authors.initials: P
authors.lastname: Zou
authors.affiliation: Chemical Biology Program, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142.
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.affiliation: Chemical Biology Program, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: From the Medical Virology Section, Laboratory of Clinical Infectious Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892-1888. Electronic address: jcohen@niaid.nih.gov.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Cohen
mesh_terms: D000813:Anilides / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology; D000069286:Bortezomib; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005814:Genes, Viral / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000472:pathogenicity; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000813:Anilides; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D017382:Reactive Oxygen Species; C474316:tubacin; D000069286:Bortezomib; C505407:CASP3 protein, human; D053148:Caspase 3; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases