WP1066 disrupts janus kinase-2 and induces caspase-dependent apoptosis in acute myelogenous leukemia cells
WP1066 disrupts janus kinase-2 and induces caspase-dependent apoptosis in acute myelogenous leukemia cells
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DOI：
10.1158/0008-5472.can-07-0593
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发表时间：
2007-12-01
期刊：
影响因子：
11.2
通讯作者：
Estrov, Zeev
中科院分区：
文献类型：
--
作者：
Ferrajoli, Alessandra;Faderl, Stefan;Estrov, Zeev
刺激急性髓细胞性白血病（AML）细胞增殖的几种细胞因子和生长因子通过激活转录因子Janus激活激酶2（JAK 2）来调节它们的信号。因此，JAK 2或其下游信号传导途径的抑制抑制AML细胞的增殖。由于（E）-3（6-溴吡啶-2-基）-2-氰基-N-（（SO-1-苯乙基）丙烯酰胺）（WP 1066）是JAK 2抑制剂AG 490的新型类似物，我们测试了其在AML细胞中的活性并研究了其作用机制。使用克隆形成试验，我们发现，虽然WP 1066对正常骨髓祖细胞的影响很小，但它抑制了从新诊断的AML患者中获得的AML集落形成细胞以及AML细胞系OCIM 2和K562的增殖。WP 1066通过诱导细胞在细胞周期的GO-G期积累来抑制OCIM 2细胞增殖。与其母体化合物AG 490类似，WP 1066抑制JAK 2的磷酸化，但与AG 490不同，WP 1066还降解JAK 2蛋白，从而阻断其下游信号转导和转录激活因子（STAT）和磷酸肌醇-3-激酶途径。这些作用导致半胱天冬酶途径的激活。温育OCIM 2和K562细胞与WPI 066激活caspase-3，诱导裂解的聚（ADP-核糖）聚合酶，并引起caspase依赖性凋亡细胞死亡。因此，WPI 066是一种有效的JAK 2抑制剂，其在AML和其他血液恶性肿瘤中的作用值得进一步研究。
Several cytokines and growth factors that stimulate the proliferation of acute myelogenous leukemia (AML) cells transduce their signals by activating the transcription factor Janus-activated kinase 2 (JAK2). Accordingly, the inhibition of JAK2 or of its downstream signaling pathways suppresses the proliferation of AML cells. Because (E)-3(6-bromopyridin-2-yl)-2-cyano-N-((S0-1-phenylethyl)acrylamide) (WP1066) is a novel analogue of the JAK2 inhibitor AG490, we tested its activity in AML cells and investigated its mechanism of action. Using clonogenic assays, we found that although WP1066 had a marginal effect on normal marrow progenitors, it inhibited the proliferation of AML colony-forming cells obtained from patients with newly diagnosed AML and that of the AML cell lines OCIM2 and K562. WP1066 inhibited OCIM2 cell multiplication by inducing accumulation of cells at the GO-G, phase of the cell cycle. Similar to its parent compound AG490, WP1066 inhibited the phosphorylation of JAK2, but unlike AG490, WP1066 also degraded JAK2 protein, thereby blocking its downstream signal transducer and activator of transcription (STAT) and phosphoinositide-3-kinase pathways. These effects resulted in the activation of the caspase pathway. Incubation of both OCIM2 and K562 cells with WPI066 activated caspase-3, induced cleavage of poly(ADP-ribose) polymerase, and caused caspase-dependent apoptotic cell death. Thus, WPI066 is a potent JAK2 inhibitor whose effects in AML and other hematologic malignancies merit further investigation.