Artemether Attenuates the Progression of Non-small Cell Lung-Cancer by Inducing Apoptosis, Cell Cycle Arrest and Promoting Cellular Senescence
Artemether Attenuates the Progression of Non-small Cell Lung-Cancer by Inducing Apoptosis, Cell Cycle Arrest and Promoting Cellular Senescence
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DOI：
10.1248/bpb.b19-00391
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发表时间：
2019-10-01
影响因子：
2
通讯作者：
Wu, Zhengzhi
中科院分区：
文献类型：
--
作者：
Chen, Jian;Huang, Xiaofei;Wu, Zhengzhi
肺癌是癌症死亡的最常见原因，其中约85%为非小细胞肺癌（NSCLC）。在这里，我们发现蒿甲醚（ART），青蒿素的天然衍生物，显着抑制非小细胞肺癌细胞的增殖，在剂量和时间依赖性的方式。高浓度ART通过下调抗凋亡蛋白B-cell lymphoma-2（Bcl-2）、细胞凋亡抑制蛋白1（cIAP 1）和细胞凋亡抑制蛋白2（cIAP 2）的水平诱导NSCLC细胞凋亡。而低浓度ART可抑制细胞周期相关基因包括细胞周期蛋白依赖性激酶1（cyclin-dependent kinase 1，CDK 1）、细胞周期蛋白依赖性激酶2（cyclin-dependent kinase 2，CDK 2）、细胞周期蛋白依赖性激酶6（cyclin-dependent kinase 6，CDK 6）、细胞周期蛋白A2（cyclin A2）、细胞周期蛋白B1（cyclin B1）和细胞周期蛋白D1（cyclin D1）的mRNA水平，导致细胞周期阻滞。此外，我们证实，低浓度的ART诱导DNA双链断裂（DSB），以及通过上调p16的mRNA和蛋白水平促进NSCLC细胞的细胞衰老。总之，ART代表了一种有前途的新的抗NSCLC候选药物，其可以通过诱导凋亡、细胞周期停滞和促进细胞衰老以p53非依赖性方式减弱NSCLC细胞的进展。
Lung cancer is the most common cause of cancer death, approximately 85% of which are non-small cell lung cancer (NSCLC). Here we found that artemether (ART), a natural derivative of artemisinin, significantly inhibits the proliferation of NSCLC cells in a dose- and time-dependent manner. We also demonstrated that high concentration of ART induces apoptosis in NSCLC cells through down-regulating the level of antiapoptotic protein B-cell lymphoma-2 (Bcl-2), cellular inhibitor of apoptosis protein 1 (cIAP1) and cellular inhibitor of apoptosis protein 2 (cIAP2). While low concentration of ART inhibits the mRNA level of cell cycle related genes including cyclin-dependent kinase 1 (CDK1), cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 6 (CDK6), cyclin A2, cyclin B1 and cyclin D1, leading to cell cycle arrest in NSCLC cells. Moreover, we confirmed that low concentration of ART induces DNA double-stranded breaks (DSBs), as well as promoting cellular senescence in NSCLC cells by up-regulating the mRNA and protein level of p16. Taken together, ART represents a promising new anti-NSCLC drug candidate that could attenuate progression of NSCLC cells in a p53-independent manner through inducing apoptosis, cell cycle arrest and promoting cellular senescence.