Pharmacological inhibition of JAK3 enhances the antitumor activity of imatinib in human chronic myeloid leukemia
Pharmacological inhibition of JAK3 enhances the antitumor activity of imatinib in human chronic myeloid leukemia
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DOI：
10.1016/j.ejphar.2018.02.022
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发表时间：
2018-04-15
影响因子：
5
通讯作者：
Sendo，Toshiaki
中科院分区：
文献类型：
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作者：
Yagi，Kenta;Shimada，Akira;Sendo，Toshiaki
伊马替尼(IMA)是CML的标准治疗方法；然而，停止IMA有时会导致疾病复发，这表明即使在分子水平完全缓解后，白血病干细胞(LSCs)仍存在于此类患者中。因此，将需要新的战略来根除LSC。Janus激酶-信号转导和转录激活因子(JAK-STAT)通路是BCR-ABL信号网络的一部分，在CML尤其是LSCs中被激活。已知JAK2与CML的生存有关，但JAK3在CML中的作用尚不清楚。用四甲基偶氮唑盐比色法检测IMA和JAK3抑制剂托法替尼对K562和KCL22的抗肿瘤作用。为了研究IMA和JAK抑制剂在CML细胞中的作用机制，我们使用流式细胞术、免疫荧光显微镜和Western blotting检测了细胞凋亡、细胞周期和JAK-STAT信号。托法替尼对JAK3的药理抑制协同增强IMA对CML细胞的抗肿瘤作用。此外，IMA加JAK抑制剂的应用减少了干细胞标记物的表达，如ABCG2和ALDH1A1。用IMA和JAK3抑制剂共同阻断JAK3可能是根除LSCs和防止CML复发的一种新的治疗策略。
Imatinib (IMA) is the standard treatment for CML; however, stopping IMA sometimes results in disease relapse, which suggests that leukemic stem cells (LSCs) remain in such patients, even after complete molecular remission has been achieved. Therefore, new strategies will be required to eradicate LSCs. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is part of the BCR-ABL signaling network, and it is activated in CML, especially in LSCs. JAK2 is known to be associated with CML survival, but the role of JAK3 in CML remains unknown. The antitumor effects of IMA and a JAK3 inhibitor, tofacitinib were examined using the MTT assay in K562 and KCL22. To investigate the mechanisms of action of IMA and the JAK inhibitors in CML cells, we examined apoptosis, the cell cycle, and JAK-STAT signaling using flow cytometry, immunofluorescent microscopy, and Western blotting. The pharmacological inhibition of JAK3 by tofacitinib synergistically enhanced the antitumor effects of IMA in CML cells. Furthermore, the administration of IMA plus a JAK inhibitor reduced the expression of stem cells markers, such as ABCG2 and ALDH1A1. Co-blocking JAK3 with IMA and a JAK3 inhibitor might represent a new treatment strategy for eradicating LSCs and preventing CML relapses.