Kawada Junichi, Zou Ping, Mazitschek Ralph, Bradner James E, Cohen Jeffrey I
From the Medical Virology Section, Laboratory of Clinical Infectious Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892-1888.
Chemical Biology Program, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142.
J Biol Chem. 2009 Jun 19;284(25):17102-17109. doi: 10.1074/jbc.M809090200. Epub 2009 Apr 22.
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.
Tubacin是一种组蛋白去乙酰化酶6的小分子抑制剂，可阻断聚集体活性。我们发现，与EB病毒（EBV）转化的淋巴母细胞（LCL）或EBV阴性的伯基特淋巴瘤（BL）细胞相比，EBV阳性的BL细胞通常在较低剂量的Tubacin作用下就会被杀死。Tubacin诱导LCL凋亡，这种凋亡可被泛半胱天冬酶抑制剂预处理所抑制，但不能被抑制活性氧的丁基羟基茴香醚所抑制。相比之下，Tubacin通过一种不依赖半胱天冬酶-3的途径杀死EBV阳性的BL细胞，该途径涉及活性氧，且可被丁基羟基茴香醚阻断。此前，我们表明蛋白酶体抑制剂硼替佐米可诱导EBV LCL凋亡，且LCL在较低剂量的硼替佐米作用下就会被杀死，而EBV阳性的BL细胞则不然。在此我们发现，硼替佐米与Tubacin联合使用具有协同作用，可杀死EBV阳性的BL细胞和LCL。Tubacin或硼替佐米与Tubacin的联合使用均未诱导EBV裂解复制。这些发现表明，蛋白酶体抑制剂与HDAC6抑制剂联合使用可能是治疗某些EBV相关B细胞淋巴瘤的有效策略。
