Cytotoxic Components from Hypericum elodeoides Targeting RXRα and Inducing HeLa Cell Apoptosis through Caspase-8 Activation and PARP Cleavage
Cytotoxic Components from Hypericum elodeoides Targeting RXRα and Inducing HeLa Cell Apoptosis through Caspase-8 Activation and PARP Cleavage
复制标题
金丝桃的细胞毒性成分靶向 RXR α 并通过 Caspase-8 激活和 PARP 裂解诱导 HeLa 细胞凋亡
DOI：
10.1021/acs.jnatprod.8b00680
复制
发表时间：
2019-05-01
影响因子：
5.1
通讯作者：
Chen, Haifeng
中科院分区：
文献类型：
--
作者：
Qiu, Daren;Zhou, Mi;Chen, Haifeng
为了寻找 RXR α 的小分子调节剂，对金丝桃进行了植物化学研究。从香菇全草中分离得到 15 种化合物，包括新的 1 和 6。 1 的绝对构型是通过比较实验和计算的 ECD 数据来确定的。化合物1和6对RXRα转录表现出浓度依赖性抑制作用，并选择性抑制HeLa细胞的增殖。蛋白质印迹分析表明，1 和 6 通过时间和剂量依赖性 PARP 裂解诱导 HeLa 细胞凋亡。 Caspase 激活测定表明，这两种化合物触发 caspase-8 激活，通过外在途径诱导细胞凋亡。分子对接结果表明1和6与RXR α-LBD的Arg319部分相互作用。与 RXR α 结合的配体在抗癌药物的发现中显示出了前景。荧光猝灭测定表明1和6与RXRα的结合，结合常数(K-D)分别拟合为68.3和14.0μM。对分离株进行了初步 SAR 研究，以增强对 RXR α 配体的了解。因此，1和6可能充当RXRα的小分子调节剂，其靶向RXRα并通过外在途径介导HeLa细胞凋亡。
To find small-molecule regulators of RXR alpha, a phytochemical study of Hypericum elodeoides was conducted. Fifteen compounds, including the new 1 and 6, were isolated from the whole plant of H. elodeoides. The absolute configuration of 1 was assigned by comparison of experimental and calculated ECD data. Compounds 1 and 6 exhibited concentration-dependent inhibitory effects on RXR alpha transcription and selectively inhibited the proliferation of HeLa cells. Western blot analysis suggested that 1 and 6 induced apoptosis of HeLa cells with time- and dose-dependent PARP cleavage. A caspase activation assay indicated that these two compounds triggered caspase-8 activation to induce apoptosis by the extrinsic pathway. Molecular docking results suggested that 1 and 6 interacted with the Arg319 moiety of RXR alpha-LBD. Ligands binding to RXR alpha have shown promise in the discovery of anticancer drugs. A fluorescence quenching assay indicated the binding of 1 and 6 to the RXR alpha with the binding constant (K-D) fitted as 68.3 and 14.0 mu M, respectively. A preliminary SAR study of the isolates was conducted to enhance the knowledge of the RXR alpha ligands. Thus, 1 and 6 might act as the small-molecule regulators of RXR alpha, which target RXR alpha and mediate HeLa cell apoptosis through the extrinsic pathways.