Sun Chao, Guo Xiao-Xi, Zhu Dan, Xiao Chuan, Bai Xiao, Li Yang, Zhan Zhuo, Li Xiang-Long, Song Zhi-Guang, Jin Ying-Hua
Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University, Changchun 130012, China.
Int J Mol Sci. 2013 Jan 4;14(1):850-70. doi: 10.3390/ijms14010850.
The novel compound JRS-15 was obtained through the chemical modification of xylocydine. JRS-15 exhibited much stronger cytotoxic and pro-apoptotic activity than its parent compound in various cancer cell lines, with IC(50) values in HeLa, HepG2, SK-HEP-1, PC-3M and A549 cells ranging from 12.42 to 28.25 µM. In addition, it is more potent for killing cancer than non-cancerous cells. Mechanistic studies showed that JRS-15 treatment arrested cell cycle at the G1/S phase, which further triggered the translocation of Bax and Bak to the mitochondria, resulting in mitochondrial membrane potential (MMP) depolarization and the subsequent release of cytochrome c and the second mitochondria-derived activator of caspase (Smac). The sequential activation of caspase-9 and caspase-3/7 and the cleavage of poly (ADP-ribose) polymerase (PARP) were observed following these mitochondrial events. Caspase-8, an initiator caspase that is required to activate the membrane receptor-mediated extrinsic apoptosis pathway was not activated in JRS-15-treated cells. Further analysis showed that the levels of the anti-apoptotic proteins Bcl-xL and XIAP were significantly reduced upon JRS-15 treatment. Furthermore, the caspase-9 inhibitor z-LEHD-fmk, the pan-caspase inhibitor z-VAD-fmk, and Bcl-xL or XIAP overexpression all effectively prevented JRS-15-induced apoptosis. Taken together, these results indicate that JRS-15 induces cancer cell apoptosis by regulating multiple apoptosis-related proteins, and this compound may therefore be a good candidate reagent for anticancer therapy.
新型化合物JRS - 15是通过对木犀草定进行化学修饰而获得的。在各种癌细胞系中，JRS - 15表现出比其母体化合物更强的细胞毒性和促凋亡活性，在HeLa、HepG2、SK - HEP - 1、PC - 3M和A549细胞中的IC(50)值范围为12.42至28.25 μM。此外，它对癌细胞的杀伤作用比对非癌细胞更强。机制研究表明，JRS - 15处理使细胞周期停滞在G1/S期，这进一步触发了Bax和Bak向线粒体的转位，导致线粒体膜电位（MMP）去极化以及随后细胞色素c和第二线粒体衍生的半胱天冬酶激活剂（Smac）的释放。在这些线粒体事件之后，观察到半胱天冬酶 - 9和半胱天冬酶 - 3/7的顺序激活以及聚（ADP - 核糖）聚合酶（PARP）的裂解。在JRS - 15处理的细胞中，激活膜受体介导的外源性凋亡途径所需的起始半胱天冬酶半胱天冬酶 - 8未被激活。进一步分析表明，JRS - 15处理后抗凋亡蛋白Bcl - xL和XIAP的水平显著降低。此外，半胱天冬酶 - 9抑制剂z - LEHD - fmk、泛半胱天冬酶抑制剂z - VAD - fmk以及Bcl - xL或XIAP的过表达均有效阻止了JRS - 15诱导的凋亡。综上所述，这些结果表明JRS - 15通过调节多种凋亡相关蛋白诱导癌细胞凋亡，因此该化合物可能是一种良好的抗癌治疗候选试剂。
