Effect of CHK1 Inhibition on CPX-351 Cytotoxicity in vitro and ex vivo.
Effect of CHK1 Inhibition on CPX-351 Cytotoxicity in vitro and ex vivo.
复制标题
CHK1 抑制对 CPX-351 体外和离体细胞毒性的影响。
DOI：
10.1038/s41598-019-40218-0
复制
发表时间：
2019
影响因子：
4.6
通讯作者：
Kaufmann,ScottH
中科院分区：
文献类型：
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作者：
Vincelette,NicoleD;Ding,Husheng;Huehls,AmeliaM;Flatten,KarenS;Kelly,RebeccaL;Kohorst,MiraA;Webster,Jonathan;Hess,AllanD;Pratz,KeithW;Karnitz,LarryM;Kaufmann,ScottH
CPX-351 是一种脂质体封装的阿糖胞苷和柔红霉素，摩尔比为 5:1，最近获得监管部门批准，用于治疗与治疗相关的急性髓系白血病 (AML) 或伴有骨髓增生异常相关变化的 AML，与标准阿糖胞苷/柔红霉素治疗相比，总体生存率有所提高。检查点激酶 1 (CHK1) 由 DNA 损伤和复制应激激活，可降低对阿糖胞苷和蒽环类药物作为单一药物的敏感性，表明 CHK1 抑制剂可能会提高 CPX-351 的有效性。目前的研究表明，CPX-351 激活 CHK1 以及 S 和 G2/M 细胞周期检查点。相反，CHK1 抑制会减弱 CPX-351 对细胞周期的影响。此外，CHK1 敲低或添加 CHK1 抑制剂（例如 MK-8776、rabusertib 或 prexasertib）可增强 CPX-351 诱导的多种 TP53 无效和 TP53 野生型 AML 细胞系的细胞凋亡。同样，CHK1 抑制增强了 CPX-351 对原发性 AML 体内样本的抗增殖作用，这为 CPX-351 可能非常适合与 CHK1 靶向药物联合使用提供了可能性。
CPX-351 is a liposomally encapsulated 5:1 molar ratio of cytarabine and daunorubicin that recently received regulatory approval for the treatment of therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes based on improved overall survival compared to standard cytarabine/daunorubicin therapy. Checkpoint kinase 1 (CHK1), which is activated by DNA damage and replication stress, diminishes sensitivity to cytarabine and anthracyclines as single agents, suggesting that CHK1 inhibitors might increase the effectiveness of CPX-351. The present studies show that CPX-351 activates CHK1 as well as the S and G2/M cell cycle checkpoints. Conversely, CHK1 inhibition diminishes the cell cycle effects of CPX-351. Moreover, CHK1 knockdown or addition of a CHK1 inhibitor such as MK-8776, rabusertib or prexasertib enhances CPX-351-induced apoptosis in multipleTP53-null andTP53-wildtype AML cell lines. Likewise, CHK1 inhibition increases the antiproliferative effect of CPX-351 on primary AML specimensex vivo, offering the possibility that CPX-351 may be well suited to combine with CHK1-targeted agents.