Combination of bendamustine and entinostat synergistically inhibits proliferation of multiple myeloma cells via induction of apoptosis and DNA damage response.
Combination of bendamustine and entinostat synergistically inhibits proliferation of multiple myeloma cells via induction of apoptosis and DNA damage response.
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苯达莫司汀和恩替司他的组合通过诱导细胞凋亡和 DNA 损伤反应协同抑制多发性骨髓瘤细胞的增殖。
DOI：
10.1016/j.canlet.2013.02.046
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发表时间：
2013-07-28
期刊：
影响因子：
9.7
通讯作者：
Liu, Bolin
中科院分区：
文献类型：
--
作者：
Cai, Bo;Lyu, Hui;Huang, Jingcao;Wang, Shuiliang;Lee, Choon-Kee;Gao, Chunji;Liu, Bolin
苯达莫司汀是一种嘌呤类似物和烷基化剂的混合分子，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。 Entinostat 是一种选择性 I 类组蛋白脱乙酰酶 (HDAC) 抑制剂，在多种癌症类型中发挥抗肿瘤活性，包括多发性骨髓瘤 (MM)。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 裂解以及 caspase-8 和 caspase-3 进行的凋亡 ELISA 和蛋白质印迹测定表明，苯达莫司汀与恩替司他组合比单独使用任一药物表现出更有效的活性，以剂量依赖性方式促进 MM 细胞发生凋亡。流式细胞术分析发现，恩替司他对不同细胞系的细胞周期进程表现出明显的影响，而苯达莫司汀主要将细胞阻滞在S期，而它们的组合则显着阻止S细胞进入G2/M期。此外，对 DNA 损伤反应的研究表明，与单独使用任一药物相比，苯达莫司汀和恩替司他的组合显着增强了磷酸化组蛋白 H2A.X (P-H2A.X)（DNA 双链断裂的霍尔标记）以及磷酸化 CHK2 (P-CHK2)。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/或恩替司他组成的治疗方案可能代表针对 MM 的新治疗策略。
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.
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影响因子：
20.3
作者：
Catley, Laurence;Weisberg, Ellen;Anderson, Kenneth C.
通讯作者：
Anderson, Kenneth C.
影响因子：
6.2
作者：
Niesvizky, Ruben;Ely, Scott;Mark, Tomer;Aggarwal, Sangeeta;Gabrilove, Janice L.;Wright, John J.;Chen-Kiang, Selina;Sparano, Joseph A.
通讯作者：
Sparano, Joseph A.
DOI：
10.1182/asheducation-2011.1.184
发表时间：
2011-12-01
期刊：
HEMATOLOGY-AMERICAN SOCIETY HEMATOLOGY EDUCATION PROGRAM
影响因子：
--
作者：
Anderson, Kenneth C.
通讯作者：
Anderson, Kenneth C.
Vorinostat与Bortezomib结合的I阶段研究，用于复发和难治性多发性骨髓瘤。
影响因子：
11.5
作者：
Badros, Ashraf;Burger, Angelika M.;Philip, Sunita;Niesvizky, Ruben;Kolla, Sarah S.;Goloubeva, Olga;Harris, Carolynn;Zwiebel, James;Wright, John J.;Espinoza-Delgado, Igor;Baer, Maria R.;Holleran, Julianne L.;Egorin, Merrill J.;Grant, Steven
通讯作者：
Grant, Steven
影响因子：
11.5
作者：
Leoni, Lorenzo M.;Bailey, Brandi;Niemeyer, Christina C.
通讯作者：
Niemeyer, Christina C.