Aggresome induction by proteasome inhibitor bortezomib and α-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells
Aggresome induction by proteasome inhibitor bortezomib and α-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells
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DOI：
10.1182/blood-2006-04-016055
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发表时间：
2006-11-15
期刊：
影响因子：
20.3
通讯作者：
Anderson, Kenneth C.
中科院分区：
文献类型：
--
作者：
Catley, Laurence;Weisberg, Ellen;Anderson, Kenneth C.
组蛋白去乙酰化酶（HDAC）抑制剂作为单一药物在多发性骨髓瘤（MM）细胞的临床前研究中显示出细胞毒性。LBH589是一种新型的羟肟酸衍生物，在低纳摩尔浓度下，通过caspase激活和聚（adp -核糖）聚合酶（PARP）裂解，诱导对常规治疗产生抗性的MM细胞凋亡。LBH589联合硼替佐米对对地塞米松（Dex）敏感和耐药的MM细胞以及原发患者MM细胞观察到显著的协同细胞毒性。低纳摩尔浓度的LBH589也能诱导α -微管蛋白超乙酰化。在硼替佐米存在的情况下，可以观察到聚集体的形成，LBH589与硼替佐米联合使用可诱导超乙酰化α -微管蛋白异常束的形成，但聚集体大小减小，细胞核凋亡。这些数据证实了HDAC抑制剂与蛋白酶体抑制剂联合使用的潜在临床益处，并为硼替佐米与LBH589联合使用协同抗mm活性的机制提供了见解。
Histone deacetylase (HDAC) inhibitors have shown cytotoxicity as single agents in preclinical studies for multiple myeloma (MM) cells. LBH589 is a novel hydroxamic acid derivative that at low nanomolar concentrations induces apoptosis in MM cells resistant to conventional therapies via caspase activation and poly(ADP-ribose) polymerase (PARP) cleavage. Significant synergistic cytotoxicity was observed with LBH589 in combination with bortezomib against MM cells that were sensitive and resistant to dexamethasone (Dex), as well as primary patient MM cells. LBH589 at low nanomolar concentrations also induced alpha-tubulin hyperacetylation. Aggresome formation was observed in the presence of bortezomib, and the combination of LBH589 plus bortezomib induced the formation of abnormal bundles of hyeracetylated alpha-tubulin but with diminished aggresome size and apoptotic nuclei. These data confirm the potential clinical benefit of combining HDAC inhibitors with proteasome inhibitors, and provide insight into the mechanisms of synergistic anti-MM activity of bortezomib in combination with LBH589.