Fan Yunpeng, Jiang Yuede, Liu Jianjun, Kang Yongxiang, Li Ruiqiao, Wang Jingyu
College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, PR China.
College of Landscape Architecture and Arts, Northwest A&F University, Yangling, Shaanxi, PR China.
Bioorg Med Chem Lett. 2016 Jan 15;26(2):380-387. doi: 10.1016/j.bmcl.2015.12.006. Epub 2015 Dec 10.
In the current study, the anti-tumor activity of Aconitum szechenyianum Gay alkaloids (ASA) and its mechanism of action were investigated. The result showed that ASA could induce apoptosis in HepG-2, Hela and A549 cells but not in normal human embryonic kidney 293A cells, and its apoptotic effect on A549 cells was stronger than those of HepG-2 and Hela cells. Moreover, the following study showed that ASA could up-regulate the expression levels of p38 and phosphorylated p38 MAPK, suggesting ASA-induced apoptosis was associated with the p38 MAPK mediated pathway. Furthermore, ASA could up-regulate TNF-R1 and DR5 via activation of p38 MAPK, thereby activating caspase 8, revealing the death receptor pathway was also involved in this process. In addition, ASA could led to a loss in the mitochondrial out membrane potential, up-regulate p53, phosphorylated p53 and Bax, down-regulate Bcl-2, release cytochrome c from the mitochondria to the cytoplasm, and activate caspase-9 and caspase-3 in A549 cells, which revealed that ASA could also induce apoptosis through the mitochondria mediated pathway. These results suggested that ASA played the anti-tumor role through the activation of p38 MAPK-, death receptor-, mitochondria- and caspase-dependent apoptotic pathways.
在本研究中，对伏毛铁棒锤生物碱（ASA）的抗肿瘤活性及其作用机制进行了研究。结果表明，ASA可诱导肝癌细胞HepG-2、宫颈癌细胞Hela和肺癌细胞A549凋亡，但对正常人类胚胎肾细胞293A无此作用，且其对A549细胞的凋亡作用强于HepG-2和Hela细胞。此外，后续研究表明，ASA可上调p38和磷酸化p38丝裂原活化蛋白激酶（MAPK）的表达水平，提示ASA诱导的凋亡与p38 MAPK介导的信号通路有关。此外，ASA可通过激活p38 MAPK上调肿瘤坏死因子受体1（TNF-R1）和死亡受体5（DR5），从而激活半胱天冬酶8（caspase 8），表明死亡受体信号通路也参与了这一过程。另外，ASA可导致A549细胞线粒体跨膜电位丧失，上调p53、磷酸化p53和促凋亡蛋白Bax，下调抗凋亡蛋白Bcl-2，使细胞色素c从线粒体释放到细胞质中，并激活caspase-9和caspase-3，这表明ASA还可通过线粒体介导的信号通路诱导凋亡。这些结果提示，ASA通过激活p38 MAPK、死亡受体、线粒体和半胱天冬酶依赖性凋亡信号通路发挥抗肿瘤作用。
