Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University.
The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital.
Biol Pharm Bull. 2019 Oct 1;42(10):1720-1725. doi: 10.1248/bpb.b19-00391. Epub 2019 Aug 3.
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 anti-apoptotic 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.
肺癌是癌症死亡的最常见原因，其中约 85%是非小细胞肺癌（NSCLC）。在这里，我们发现青蒿素的天然衍生物蒿甲醚（ART）以剂量和时间依赖的方式显著抑制 NSCLC 细胞的增殖。我们还证明，高浓度的 ART 通过下调抗凋亡蛋白 B 细胞淋巴瘤-2（Bcl-2）、细胞凋亡抑制蛋白 1（cIAP1）和细胞凋亡抑制蛋白 2（cIAP2）的水平诱导 NSCLC 细胞凋亡。而低浓度的 ART 抑制包括周期蛋白依赖性激酶 1（CDK1）、周期蛋白依赖性激酶 2（CDK2）、周期蛋白依赖性激酶 6（CDK6）、细胞周期蛋白 A2、细胞周期蛋白 B1 和细胞周期蛋白 D1 等细胞周期相关基因的 mRNA 水平，导致 NSCLC 细胞周期停滞。此外，我们证实低浓度的 ART 通过上调 p16 的 mRNA 和蛋白水平诱导 DNA 双链断裂（DSBs），并促进 NSCLC 细胞衰老。综上所述，ART 代表了一种有前途的新型抗 NSCLC 药物候选物，它可以通过诱导细胞凋亡、细胞周期停滞和促进细胞衰老来减轻 NSCLC 细胞的进展，而不依赖于 p53。
