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: Junichi Kawada, Ping Zou, Ralph Mazitschek, James E Bradner, Jeffrey I Cohen
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 284 Issue 25 Pg. 17102-17109 (Jun 19 2009) ISSN: 1083-351X [Electronic] United States
• PMID: 19386607 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Anilides
• Boronic Acids
• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Protease Inhibitors
• Pyrazines
• Reactive Oxygen Species
• tubacin
• Bortezomib
• CASP3 protein, human
• Caspase 3
• HDAC6 protein, human
• Histone Deacetylase 6
• Histone Deacetylases

Topics

• Anilides (administration & dosage, pharmacology)
• Apoptosis (drug effects)
• B-Lymphocytes (drug effects, metabolism, pathology, virology)
• Boronic Acids (administration & dosage, pharmacology)
• Bortezomib
• Burkitt Lymphoma (drug therapy, metabolism, pathology, virology)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Transformation, Viral
• Drug Synergism
• Enzyme Inhibitors (administration & dosage, pharmacology)
• Genes, Viral (drug effects)
• Herpesvirus 4, Human (genetics, pathogenicity)
• Histone Deacetylase 6
• Histone Deacetylase Inhibitors
• Histone Deacetylases
• Humans
• Hydroxamic Acids (administration & dosage, pharmacology)
• Protease Inhibitors (administration & dosage, pharmacology)
• Pyrazines (administration & dosage, pharmacology)
• Reactive Oxygen Species (metabolism)