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首页> 外文期刊>Apoptosis >Interruption of the MEK/ERK signaling cascade promotes dihydroartemisinin-induced apoptosis in vitro and in vivo
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Interruption of the MEK/ERK signaling cascade promotes dihydroartemisinin-induced apoptosis in vitro and in vivo

机译：MEK / ERK信号级联的中断在体外和体内促进双氢青蒿素诱导的细胞凋亡

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摘要

Artemisinin, the active principle of the Chinese medicinal herb Artemisia annua, and its derivatives (i.e. dihydroartemisinin, DHA) were reported to exhibit anti-tumor activity both in vitro and in vivo. The purpose of the present study was to investigate the functional role of Mitogen-Activated Protein Kinase (MEK)/Extracellular signal-regulated protein Kinase (ERK) signaling cascade in dihydroartemisinin (DHA)-induced apoptosis in human leukemia cells in vitro and anti-leukemic activity in vivo. Human leukemia cells were treated with DHA in dose- and time-dependent manners, after which apoptosis, caspase activation, Mcl-1 expression, and cell signaling pathways were evaluated. Parallel studies were performed in AML and ALL primary human leukemia cells. In vivo anti-leukemic activity mediated by DHA was also investigated using U937 xenograft mouse model. Exposure of DHA resulted in a pronounced increase in apoptosis in both transformed and primary human leukemia cells but not in normal peripheral blood mononuclear cells. DHA-induced apoptosis was accompanied by caspase activation, cytochrome c release, Mcl-1 down-regulation, as well as MEK/ERK inactivation. Pretreatment with MEK inhibitor PD98059, which potentiated DHA-mediated MEK and ERK inactivation, intensified DHA-mediated apoptosis. Conversely, enforced expression of a constitutively active MEK1 attenuated DHA-induced apoptosis. Furthermore, DHA-mediated inhibition of tumor growth of mouse U937 xenograft was associated with induction of apoptosis and inactivation of ERK. The findings in the present study showed that DHA-induced apoptosis in human leukemia cells in vitro and exhibited an anti-leukemic activity in vivo through a process that involves MEK/ERK inactivation, Mcl-1 down-regulation, culminating in cytochrome c release and caspase activation.
机译：据报道，青蒿素是中草药青蒿的有效成分，其衍生物（即双氢青蒿素，DHA）在体外和体内均表现出抗肿瘤活性。本研究的目的是研究丝裂素活化蛋白激酶（MEK）/细胞外信号调节蛋白激酶（ERK）信号级联在双氢青蒿素（DHA）诱导的人白血病细胞体外凋亡中的功能和抗-体内的白血病活性。用DHA以剂量和时间依赖性方式处理人白血病细胞，然后评估其凋亡，胱天蛋白酶激活，Mcl-1表达和细胞信号通路。在AML和ALL原发性人类白血病细胞中进行了平行研究。还使用U937异种移植小鼠模型研究了DHA介导的体内抗白血病活性。暴露的DHA导致转化的和原代人白血病细胞的凋亡均显着增加，而正常外周血单核细胞却没有。 DHA诱导的细胞凋亡伴随caspase激活，细胞色素c释放，Mcl-1下调以及MEK / ERK失活。用MEK抑制剂PD98059预处理可增强DHA介导的MEK和ERK失活，从而增强DHA介导的细胞凋亡。相反，组成型活性MEK1的强制表达减弱了DHA诱导的细胞凋亡。此外，DHA介导的小鼠U937异种移植瘤生长的抑制与细胞凋亡的诱导和ERK的失活有关。本研究的发现表明，DHA在体外诱导人白血病细胞凋亡，并通过涉及MEK / ERK失活，Mcl-1下调，最终导致细胞色素c释放和释放的过程，在体内表现出抗白血病活性。半胱天冬酶激活。

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