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首页> 外文期刊>Cancer letters >Combination of bendamustine and entinostat synergistically inhibits proliferation of multiple myeloma cells via induction of apoptosis and DNA damage response
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Combination of bendamustine and entinostat synergistically inhibits proliferation of multiple myeloma cells via induction of apoptosis and DNA damage response

机译：苯达莫司汀和恩替司他的组合通过诱导凋亡和DNA损伤反应协同抑制多发性骨髓瘤细胞的增殖

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摘要

Bendamustine, a hybrid molecule of purine analog and alkylator, induces cell death by activation of apoptosis, DNA damage response, and mitotic catastrophe. Entinostat, a selective class I inhibitor of histone deacetylase (HDAC), exerts anti-tumor activity in various cancer types, including multiple myeloma (MM). We sought to determine the combinatorial effects of bendamustine and entinostat on MM cells. Cell growth assays showed that bendamustine or entinostat inhibited proliferation in a dose-dependent manner, and their combinations synergistically induced growth inhibition in all MM cells tested. An apoptotic-ELISA and western blot assays on PARP cleavage and caspase-8 and caspase-3 revealed that bendamustine in combination with entinostat exhibited a much more potent activity than either agent alone to promote the MM cells undergoing apoptosis in a dose-dependent manner. Flow cytometric analysis found that entinostat exhibited distinct effects on cell cycle progression in different lines and bendamustine mainly arrested the cells at S phase, whereas their combinations dramatically blocked the S cells entering G2/M phase. Furthermore, studies on DNA damage response indicated that phospho-histone H2A.X (P-H2A.X), a hall marker of DNA double strand break, along with phosphorylated CHK2 (P-CHK2) was significantly enhanced by the combinations of bendamustine and entinostat as compared to either agent alone. These molecular changes were correlated with the increases in mitotic catastrophe. Collectively, our data demonstrate that bendamustine in combination with entinostat exhibit potent anti-proliferative/anti-survival activity in MM cells via induction of apoptosis and DNA damage response. Regimens consisting of bendamustine and/or entinostat may represent novel therapeutic strategies against MM.
机译：苯达莫司汀是嘌呤类似物和烷化剂的杂合分子，通过激活细胞凋亡，DNA损伤反应和有丝分裂灾难来诱导细胞死亡。恩替司他是组蛋白脱乙酰基酶（HDAC）的选择性I类抑制剂，可在多种癌症类型（包括多发性骨髓瘤（MM））中发挥抗肿瘤活性。我们试图确定苯达莫司汀和恩替司他对MM细胞的组合作用。细胞生长测定表明苯达莫司汀或恩替司他以剂量依赖性方式抑制增殖，并且它们的组合在所有测试的MM细胞中协同诱导生长抑制。对PARP裂解和caspase-8和caspase-3进行的细胞凋亡ELISA和Western blot分析表明，苯达莫司汀联合恩替司他具有比单独使用任何一种试剂更强的活性，以剂量依赖的方式促进MM细胞凋亡。流式细胞仪分析发现恩替司他在不同细胞系中对细胞周期进程表现出明显的影响，苯达莫司汀主要将细胞停滞在S期，而它们的组合则极大地阻止了S细胞进入G2 / M期。此外，对DNA损伤反应的研究表明，苯达莫司汀和苯达莫司汀的组合显着增强了DNA双链断裂的标志物磷酸组蛋白H2A.X（P-H2A.X）和磷酸化的CHK2（P-CHK2）。恩替司他与任何一种单独药物相比。这些分子变化与有丝分裂灾难的增加相关。总的来说，我们的数据表明苯达莫司汀与恩替司他联合通过诱导细胞凋亡和DNA损伤反应，在MM细胞中表现出有效的抗增殖/抗存活活性。由苯达莫司汀和/或恩替司他组成的方案可能代表针对MM的新型治疗策略。

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