Rudy Anita, López-Antón Nancy, Dirsch Verena M, Vollmar Angelika M
Department of Pharmacy, University of Munich, Munich, Germany.
J Nat Prod. 2008 Mar;71(3):482-6. doi: 10.1021/np070534e. Epub 2008 Feb 8.
The cephalostatins, bis-steroidal natural products from the marine tube worm Cephalodiscus gilchristi, were isolated by Dr. G. R. Pettit and his group. These compounds show a unique cytotoxicity profile in the in vitro screen of the National Cancer Institute, suggesting a novel mechanism of action. Indeed, cephalostatin 1 ( 1) is an extremely powerful agent that acts via an unusual apoptosis pathway. It induces selective Smac/DIABLO, but no cytochrome c release from mitochondria. Nevertheless, caspase-9 is required for apoptosis induction. Interestingly, caspase-9 is activated without the participation of the apoptosome, leading to the question of its mechanism of activation. We found that endoplasmic reticulum stress-associated caspase-4 contributes to nonclassical cephalostatin-mediated caspase-9 activation, additionally pointing out the unusual pathway used by this substance. Cephalostatin 1 ( 1), therefore, provides a very good tool to discover novel apoptotic pathways, which might be important in the understanding and treatment of chemo-resistant cancer.
头盘菌素是从海洋管栖蠕虫吉尔氏头盘虫中分离出的双甾体天然产物，由G. R. 佩蒂特博士及其团队完成。这些化合物在美国国立癌症研究所的体外筛选中显示出独特的细胞毒性特征，提示其作用机制新颖。事实上，头盘菌素1（1）是一种极其强效的药物，通过一条不同寻常的凋亡途径发挥作用。它能诱导选择性的Smac/DIABLO释放，但不会使细胞色素c从线粒体中释放。然而，凋亡诱导需要caspase-9。有趣的是，caspase-9的激活无需凋亡小体的参与，这就引发了其激活机制的问题。我们发现内质网应激相关的caspase-4促成了非经典的头盘菌素介导的caspase-9激活，这也进一步指出了该物质所采用的不同寻常的途径。因此，头盘菌素1（1）为发现新的凋亡途径提供了一个很好的工具，这对于理解和治疗化疗耐药性癌症可能具有重要意义。
