The class-I HDAC inhibitor MGCD0103 induces apoptosis in Hodgkin lymphoma cell lines and synergizes with proteasome inhibitors by an HDAC6-independent mechanism
The class-I HDAC inhibitor MGCD0103 induces apoptosis in Hodgkin lymphoma cell lines and synergizes with proteasome inhibitors by an HDAC6-independent mechanism
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DOI：
10.1111/j.1365-2141.2010.08342.x
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发表时间：
2010-11-01
影响因子：
6.5
通讯作者：
Younes, Anas
中科院分区：
文献类型：
--
作者：
Buglio, Daniela;Mamidipudi, Vidya;Younes, Anas
最近报道，泛HDAC抑制剂对组蛋白去乙酰化酶6（HDAC 6）依赖性攻击体功能的抑制是蛋白酶体抑制剂和HDAC抑制剂在多种肿瘤类型中协同活性的关键机制。由于这些组合在体内诱导显著的血小板减少症，我们研究了毒性较低的同种型选择性HDAC抑制剂是否仍然可以与蛋白酶体抑制剂协同作用，如果是这样，通过什么机制。在这里，我们表明，I类HDAC抑制剂，MGCD 0103，在霍奇金淋巴瘤（HL）细胞系中具有有效的抗增殖活性。此外，MG CD 0103诱导肿瘤坏死因子α（TNF-α）表达和分泌，这与核因子（NF）-κ B活化相关。通过短干扰mRNA选择性抑制TNF-α表达，或通过蛋白酶体抑制剂抑制MGCD 0103诱导的NF-κ B活化，可增强MGCD 0103诱导的细胞死亡。因此，我们的研究结果表明，MGCD 0103可能通过HDAC 6非依赖性机制与蛋白酶体抑制剂协同作用，为探索这种潜在毒性较低的联合治疗淋巴瘤提供了机制依据。
P>Inhibition of histone deacetylase 6 (HDAC6)-dependent aggresome function by pan HDAC inhibitors was recently reported to be a key mechanism underlying the synergistic activity between proteasome inhibitors and HDAC inhibitors in a variety of tumour types. Because these combinations induce significant thrombocytopenia in vivo, we examined whether less toxic, isotype-selective HDAC inhibitors may still synergize with proteasome inhibitors, and if so, by what mechanisms. Here, we showed that the class I HDAC inhibitor, MGCD0103, has a potent antiproliferative activity in Hodgkin lymphoma (HL) cell lines. Furthermore, MGCD0103 induced tumour necrosis factor alpha (TNF-alpha) expression and secretion, which was associated with nuclear factor (NF)-kappa B activation. Selective inhibition of TNF-alpha expression by short interfering mRNA, or inhibition of MGCD0103-induced NF-kB activation by proteasome inhibitors enhanced MGCD0103-induced cell death. Thus, our results demonstrate that MGCD0103 may synergize with proteasome inhibitors by HDAC6-independent mechanisms, providing mechanistic rationale for exploring this potentially less toxic combination for the treatment of lymphoma.