Bortezomib and SAHA Synergistically Induce ROS-Driven Caspase-Dependent Apoptosis of Nasopharyngeal Carcinoma and Block Replication of Epstein-Barr Virus
Bortezomib and SAHA Synergistically Induce ROS-Driven Caspase-Dependent Apoptosis of Nasopharyngeal Carcinoma and Block Replication of Epstein-Barr Virus
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DOI：
10.1158/1535-7163.mct-12-0811
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发表时间：
2013-05-01
影响因子：
5.7
通讯作者：
Chiang, Alan K. S.
中科院分区：
文献类型：
--
作者：
Hui, Kwai Fung;Lam, Benjamin H. W.;Chiang, Alan K. S.
蛋白酶体抑制剂硼替佐米和组蛋白去乙酰化酶抑制剂辛二酰苯胺异羟肟酸（SAHA）的新型药物组合在鼻咽癌（NPC）中进行了体外和体内试验。测定了不同浓度硼替佐米和SAHA对鼻咽癌细胞增殖抑制的量效关系。探讨了EB病毒（EBV）诱导细胞凋亡的机制及其对细胞裂解周期激活的影响。硼替佐米和SAHA的组合（硼替佐米/SAHA）协同诱导一组NPC细胞系的杀伤。与单独使用任何一种药物相比，硼替佐米/SAHA治疗后检测到sub-G（1）、Annexin V阳性和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）阳性细胞群明显增加。同时，观察到PARP、半胱天冬酶-3、-7、-8和-9的蛋白水解裂解、活性氧（ROS）产生和半胱天冬酶-8依赖性组蛋白乙酰化显著增强。ROS清除剂N-乙酰半胱氨酸可减弱bortezelatin/SAHA的凋亡作用，而caspase抑制剂Z-VAD-FMK可显著抑制凋亡而不减少ROS的产生。硼替佐米抑制SAHA对EBV复制的诱导，并消除NPC细胞中感染性病毒颗粒的产生。此外，硼替佐米/SAHA有效地诱导细胞凋亡，并抑制鼻咽癌裸鼠移植瘤的生长。总之，硼替佐米和SAHA的新型药物组合在体外和体内杀死NPC细胞方面具有高度协同作用。细胞死亡的主要机制是ROS驱动的caspase依赖性凋亡。硼替佐米拮抗SAHA对NPC细胞中EBV裂解周期的激活。本研究为鼻咽癌患者联合用药方案的临床试验提供了有力的依据。(c)2013年AACR。
A novel drug combination of a proteasome inhibitor, bortezomib, and a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), was tested in nasopharyngeal carcinoma (NPC), both in vitro and in vivo. Dose-response of different concentrations of bortezomib and SAHA on inhibition of cell proliferation of NPC was determined. Mechanisms of apoptosis and effects on lytic cycle activation of Epstein-Barr virus (EBV) were investigated. Combination of bortezomib and SAHA(bortezomib/SAHA) synergistically induced killing of a panel of NPC cell lines. Pronounced increase in sub-G(1), Annexin V-positive, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cell populations were detected after treatment with bortezomib/SAHA when compared with either drug alone. Concomitantly, markedly augmented proteolytic cleavage of PARP, caspase-3, -7, -8, and -9, reactive oxygen species (ROS) generation, and caspase-8-dependent histone acetylation were observed. ROS scavenger, N-acetyl cysteine, diminished the apoptotic effects of bortezomib/SAHA, whereas caspase inhibitor Z-VAD-FMK significantly suppressed the apoptosis without decreasing the generation of ROS. Bortezomib inhibited SAHA's induction of EBV replication and abrogated production of infectious viral particles in NPC cells. Furthermore, bortezomib/SAHA potently induced apoptosis and suppressed the growth of NPC xenografts in nude mice. In conclusion, the novel drug combination of bortezomib and SAHA is highly synergistic in the killing of NPC cells in vitro and in vivo. The major mechanism of cell death is ROS-driven caspase-dependent apoptosis. Bortezomib antagonizes SAHA's activation of EBV lytic cycle in NPC cells. This study provides a strong basis for clinical testing of the combination drug regimen in patients with NPC. (c) 2013 AACR.