Entinostat combined with Fludarabine synergistically enhances the induction of apoptosis in TP53 mutated CLL cells via the HDAC1/HO-1 pathway.
Entinostat combined with Fludarabine synergistically enhances the induction of apoptosis in TP53 mutated CLL cells via the HDAC1/HO-1 pathway.
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DOI：
10.1016/j.lfs.2019.116583
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发表时间：
2019-09
期刊：
影响因子：
6.1
通讯作者：
Zheng Zhou;Q. Fang;Peifan Li;D. Ma;Nana Zhe;M. Ren;Bingqing Chen;Zhengchang He;Jun Wang;Qin Zhong;Jishi Wang
中科院分区：
文献类型：
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作者：
Zheng Zhou;Q. Fang;Peifan Li;D. Ma;Nana Zhe;M. Ren;Bingqing Chen;Zhengchang He;Jun Wang;Qin Zhong;Jishi Wang
TP 53突变是慢性淋巴细胞白血病（CLL）预后不良的指标。更糟糕的是，具有TP 53突变的CLL患者与当前化疗剂（如氟达拉滨）的疗效差相关。本研究证实HDAC 1在TP 53突变的CLL患者中高表达，与预后不良及耐药密切相关。随后，我们证明了恩替司他（HDAC 1抑制剂）与氟达拉滨的组合显著诱导TP 53突变CLL细胞的凋亡。其机制与上调促凋亡蛋白Bax，下调HDAC 1、HO-1和BCL-2蛋白有关。更重要的是，我们还证实了HDAC 1的上调可以通过激活HDAC 1/P38/HO-1通路来抵抗TP 53突变CLL细胞中恩替司他诱导的凋亡。在体内实验中，我们发现恩替司他联合氟达拉滨在异种移植小鼠模型中显著诱导肿瘤细胞凋亡并延长存活时间。最后，结合体外和体内实验，我们首次证明恩替司他与氟达拉滨组合对TP 53突变CLL细胞中的凋亡诱导具有协同作用。总之，我们为预后不良的CLL患者的治疗提供了有价值的临床前实验证据，特别是TP 53突变。
TP53 mutation is an indicator of poor prognostic in chronic lymphocytic leukemia (CLL). Worse still, CLL patients with TP53 mutation are associated with poor efficacy to current chemotherapeutic, such as Fludarabine. Here, we confirmed that high expression of HDAC1 in CLL patients with TP53 mutation, which is closely related to poor prognosis and drug-resistance. Subsequently, we demonstrated Entinostat (HDAC1 inhibitor) combination with Fludarabine significantly induced apoptosis in TP53 mutations CLL cells. Its mechanism was associated with up-regulation of the pro-apoptotic protein Bax and the down-regulation of HDAC1, HO-1 and BCL-2 proteins. More importantly, we also confirmed that upregulation of HDAC1 could resistant Entinostat-induced apoptosis in TP53 mutations CLL cells by activating the HDAC1/P38/HO-1 pathway. In vivo, we found that Entinostat combination with Fludarabine significantly induced tumor cells apoptosis and prolong survival time in xenograft mouse model. Finally, combining vitro and vivo experiments, we presented the first demonstration that Entinostat combination with Fludarabine had a synergistic effect on the induction of apoptosis in TP53 mutations CLL cells. In conclusion, we provide valuable pre-clinical experimental evidence for the treatment of CLL patients with poor prognosis, especially for TP53 mutations.