Biochemical and computational evaluation of Triptolide-induced cytotoxicity against NSCLC
Biochemical and computational evaluation of Triptolide-induced cytotoxicity against NSCLC
复制标题
雷公藤甲素诱导的非小细胞肺癌细胞毒性的生化和计算评估
DOI：
10.1016/j.biopha.2018.04.198
复制
发表时间：
2018-07-01
影响因子：
7.5
通讯作者：
Zhang, Lu-Yong
中科院分区：
文献类型：
--
作者：
Hamdi, Aida M.;Jiang, Zhen-Zhou;Zhang, Lu-Yong
雷公藤内酯醇是从中药雷公藤中分离得到的主要活性成分。尽管越来越多的兴趣和过多的报告讨论这种二萜类化合物的药理活性，没有明确的共识，关于其细胞靶点和完整的作用机制已达成一致，在目前的工作中，结合在体外和在硅片的方法被用来评估雷公藤内酯醇对非小细胞肺癌（NSCLC）的生物活性。在体外，雷公藤内酯醇处理诱导非小细胞肺癌细胞系凋亡，并下调AKT，mTOR和p70 S6 K的磷酸化。雷公藤内酯醇还通过损害葡萄糖利用、HKII、谷胱甘肽和NRF 2水平影响细胞糖酵解以及抗氧化反应。分子对接的结果检查了雷公藤甲素和AKT之间可能的相互作用，并预测AKT-1结构的变构结合。分子动力学模拟进一步用于评估雷公藤内酯醇的最佳构象和AKT形成的复合物的稳定性。这些发现为雷公藤内酯醇对NSCLC的抗癌作用提供了一种有见地的方法，并强调了AKT/mTOR HKII抑制的可能新作用。
Triptolide is the major bioactive component isolated from the Chinese Medicinal plant Tripterygium wilfordii. Despite the growing interest and the plethora of reports discussing the pharmacological activity of this diterpenoid, no clear consensus regarding its cellular targets and full mechanism of action has been reached.In the present work, a combined in vitro and in silico approach was used to evaluate the biological activity of Triptolide on Non-small cell lung cancer (NSCLC). In vitro, Triptolide treatment induced apoptosis in NSCLC cell lines and down-regulated the phosphorylation of AKT, mTOR, and p70S6K. Triptolide also impacted cellular glycolysis as well as the antioxidant response through the impairment of glucose utilization, HKII, glutathione, and NRF2 levels. Molecular docking results examined the possible interactions between Triptolide and AKT and predicted an allosteric binding to AKT-1 structure. Molecular dynamics simulations were further used to evaluate the stability of the complex formed by Triptolide's best conformer and AKT. These findings provide an insightful approach to the anticancer effect of Triptolide against NSCLC and highlight a possible new role for AKT/mTOR HKII inhibition.