Key Laboratory of Resources and Chemistry of Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, PR China.
School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, PR China.
Biomed Pharmacother. 2018 Feb;98:619-625. doi: 10.1016/j.biopha.2017.12.057. Epub 2017 Dec 29.
Brevilin A is a sesquiterpene lactone isolated from Centipeda minima and possesses inhibitory effects on proliferation of various tumor cells. In this study, Brevilin A inhibitory effect on proliferation and its molecular mechanism of action were investigated both in vivo and in vitro in colon adenocarcinoma CT26 cells. The results indicated that the inhibitory effect of Brevilin A in CT26 proliferation was dose-dependent and this effect was due to apoptosis. Furthermore, Brevilin A increased ROS levels, decreased mitochondrial membrane potential (MMP) and induced apoptosis of CT26 cell in a dose-dependent manner. Apoptosis induced by Brevilin A was higher than that induced by adriamycin under the same dose. Cleaved-caspase-8, cleaved-caspase-9 and cleaved-caspase-3 were up-regulated after Brevilin A treatment, together with an increase of Bax protein expression, while Bcl-2 was reduced. Further investigation revealed that Brevilin A inhibited the phosphorylation of PI3K, AKT and mTOR and promoted the expressions of autophagy-related proteins LC3-II, Beclin1 and Atg5 and consequent formation of autophagosomes, whereas 3-methyladenine (3-MA), a type III PI3K inhibitor, inhibited autophagosomes formation induced by Brevilin A. In vivo investigation suggested that Brevilin A significantly inhibited the growth of CT26 tumor compared to adriamycin and concurrently promoted the expressions of LC3-II and cleaved-caspase-3 in tumor tissues. Our results demonstrated that the anti-tumor activity of Brevilin A was mainly achieved by the induction of cell apoptosis and autophagy, suggesting a promising potential as antitumor drug against colon adenocarcinoma.
布瑞维林 A 是从铺地蜈蚣中分离得到的一种倍半萜内酯，具有抑制多种肿瘤细胞增殖的作用。本研究采用体内和体外实验方法，探讨了布瑞维林 A 对结肠腺癌 CT26 细胞增殖的抑制作用及其分子作用机制。结果表明，布瑞维林 A 对 CT26 增殖的抑制作用呈剂量依赖性，这种作用是由于细胞凋亡所致。此外，布瑞维林 A 以剂量依赖性方式增加 ROS 水平、降低线粒体膜电位（MMP）并诱导 CT26 细胞凋亡。在相同剂量下，布瑞维林 A 诱导的细胞凋亡高于阿霉素。布瑞维林 A 处理后，cleaved-caspase-8、cleaved-caspase-9 和 cleaved-caspase-3 表达上调，Bax 蛋白表达增加，Bcl-2 减少。进一步研究表明，布瑞维林 A 抑制了 PI3K、AKT 和 mTOR 的磷酸化，并促进了自噬相关蛋白 LC3-II、Beclin1 和 Atg5 的表达以及自噬体的形成，而 3-甲基腺嘌呤（3-MA）是一种 III 型 PI3K 抑制剂，可抑制布瑞维林 A 诱导的自噬体形成。体内研究表明，与阿霉素相比，布瑞维林 A 显著抑制 CT26 肿瘤的生长，同时促进肿瘤组织中 LC3-II 和 cleaved-caspase-3 的表达。我们的研究结果表明，布瑞维林 A 的抗肿瘤活性主要通过诱导细胞凋亡和自噬来实现，表明其作为抗结肠腺癌药物具有广阔的应用前景。
