Napabucasin (BBI608) eliminate AML cells in vitro and in vivo via inhibition of Stat3 pathway and induction of DNA damage
Napabucasin (BBI608) eliminate AML cells in vitro and in vivo via inhibition of Stat3 pathway and induction of DNA damage
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Napabucasin (BBI608) 通过抑制 Stat3 通路和诱导 DNA 损伤在体外和体内消除 AML 细胞
DOI：
10.1016/j.ejphar.2019.05.020
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发表时间：
2019-07-15
影响因子：
5
通讯作者：
Xu, Bing
中科院分区：
文献类型：
--
作者：
Bi, Silei;Chen, Kai;Xu, Bing
急性髓系白血病（AML）是一种造血干细胞的异质性恶性肿瘤，尽管近年来化疗和干细胞移植方案有所改善，但临床结局仍不佳。因此，临床上迫切需要新的治疗药物以延长AML患者的无病生存期。在这里，我们报告BBI 608在体外对不同的AML细胞系和从AML患者体内获得的原代样品具有高度活性，并且在AML异种移植模型中体内有效。BBI 608的抗AML作用与抑制Stat 3通路和诱导DNA损伤密切相关。值得注意的是，BBI 608与Bcl-2抑制剂（即，ABT-199）在BBI 608抗性细胞系Kasumi-1中发挥显著增强的抗白血病作用。总之，目前的研究结果表明，BBI 608可能是AML治疗的潜在候选药物。
Acute myeloid leukemia (AML) is a heterogeneous malignancy of hematopoietic stem cells with poor clinical outcome despite recent improvements in chemotherapy and stem cell transplantation regimens. Thus, new therapeutic agents are urgently needed in order to prolong the disease-free survival of AML patients in clinic. Here, we report that BBI608 is highly active against diverse AML cell lines in vitro and primary samples obtained from patients with AML ex vivo, as well as effective in vivo in AML xenograft models. Meanwhile, the anti-AML property of BBI608 is closely associated with the inhibition of Stat3 pathway and induction of DNA damage. Of note, BBI608 combined with Bcl-2 inhibitor (i.e., ABT-199) exerts a significantly enhanced anti-leukemia effect in BBI608-resistant cell line Kasumi-1. Together, the present findings suggest that BBI608 might represent a potential candidate agent for AML treatment.