Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in mantle cell lymphoma
Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in mantle cell lymphoma
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DOI：
10.1111/j.1600-0609.2007.00995.x
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发表时间：
2008-02-01
影响因子：
3.1
通讯作者：
Sezer, Orhan
中科院分区：
文献类型：
--
作者：
Heider, Ulrike;von Metzler, Ivana;Sezer, Orhan
目的：套细胞淋巴瘤（MCL）是一种难以治愈的B细胞淋巴瘤，迫切需要新的治疗策略。我们评估了蛋白酶体抑制剂硼替佐米和组蛋白去乙酰化酶抑制剂（HDACi）辛二酰苯胺异羟肟酸（SAHA）联合治疗对MCL的影响。硼替佐米通过靶向蛋白酶体起作用，并且-在其他机制中-导致核因子-κ B（NF-κ B）活性降低。HDACi促进组蛋白乙酰化，并且还干扰NF-κ B信号传导。方法：人MCL细胞系（JeKo-1，Granta-519和Hbl-2）暴露于硼替佐米和/或SAHA。分别通过MTT和膜联蛋白-V测定来定量细胞活力和凋亡。使用荧光团H（2）DCFDA分析活性氧（ROS）。此外，定量活化的半胱天冬酶、蛋白酶体和NF-κ B活性。结果如下：与硼替佐米和SAHA的组合孵育产生协同细胞毒性效应，如使用Chou和Talalay的中值效应方法的组合指数值< 1所示。与单一药物相比，两种抑制剂的组合导致细胞凋亡的强烈增加，并伴随着增强的ROS生成，而单独的每种药物仅适度诱导ROS。自由基清除剂N-乙酰-1-半胱氨酸可阻断ROS的产生，显著减少细胞凋亡。此外，硼替佐米和SAHA共同暴露导致caspase-3、-8和-9活性增加，蛋白酶体活性显著降低，NF-κ B活性降低。结论：这是第一个报告，证明SAHA和硼替佐米协同诱导MCL细胞凋亡。这些数据建立了使用蛋白酶体和组蛋白去乙酰化酶联合抑制治疗MCL的临床试验框架。
Objectives: Mantle cell lymphoma (MCL) is an incurable B cell lymphoma, and novel treatment strategies are urgently needed. We evaluated the effects of combined treatment with the proteasome inhibitor bortezomib and the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) on MCL. Bortezomib acts by targeting the proteasome, and - among other mechanisms - results in a reduced nuclear factor-kappa B (NF-kappa B) activity. HDACi promote histone acetylation, and also interfere with NF-kappa B signaling. Methods: Human MCL cell lines (JeKo-1, Granta-519 and Hbl-2) were exposed to bortezomib and/or SAHA. Cell viability and apoptosis were quantified by the MTT and annexin-V assay, respectively. Reactive oxygen species (ROS) were analyzed using the fluorophore H(2)DCFDA. In addition, activated caspases, proteasome- and NF-kappa B activity were quantified. Results: Combined incubation with bortezomib and SAHA resulted in synergistic cytotoxic effects, as indicated by combination index values < 1 using the median effect method of Chou and Talalay. The combination of both inhibitors led to a strong increase in apoptosis as compared to single agents and was accompanied by enhanced ROS generation, while each agent alone only modestly induced ROS. The free radical scavenger N-acetyl-1-cysteine blocked the ROS generation and reduced the apoptosis significantly. In addition, coexposure of bortezomib and SAHA led to increased caspase-3, -8 and -9 activity, marked reduction of proteasome activity and decrease of NF-kappa B activity. Conclusions: This is the first report giving evidence that SAHA and bortezomib synergistically induce apoptosis in MCL cells. These data build the framework for clinical trials using combined proteasome and histone deacetylase inhibition in the treatment of MCL.