强心苷类化合物具有明确的抗癌功效，但其作用机制不明确。前期工作中，我们发现该类物质能够通过诱导核孤儿受体Nur77表达及其转位至线粒体，诱导肿瘤细胞凋亡达到其抗肿瘤效果；同时研究表明其诱导肿瘤细胞凋亡不依赖于对其传统作用靶标Na+/K+-ATP酶的作用，同时对该酶活性也没有影响，提示可能不具有心脏毒性，同时存在新的作用靶标，是一种新的抗癌作用机制。研究还发现，强心苷结构中糖链对于其诱导Nur77蛋白表达和抗癌活性至关重要，不同的糖基取代其活性差异显著。本课题拟基于天然产物骨架和结构特征对强心苷糖基片段进行结构修饰和改造，研究糖链变化对其抗肿瘤活性及心脏毒性的影响，揭示其抗肿瘤的化学结构基础；同时优选出低毒性的活性化合物，对其进行生物素标记，采用蛋白质活性表达谱技术“钓取”与强心苷直接作用的靶标蛋白，探讨其诱导肿瘤细胞凋亡的作用机制。以上研究将为寻找新的、高效低毒的强心苷类抗癌药物提供依据。

Cardiac glycosides possess definite anticancer effects, but its mechanism of action is not fully elucidated. Our previous studies revealed that both induction of Nur77 expression and its subsequent translocation to mitochondria from the nucleus to the cytoplasm are critical events in apoptosis induction by cardiac glycosides in cancer cells. Further studies suggested that induction of apoptosis by cardiac glycosides was independent on the existence of their traditional target Na+/K+-ATPase and they also didn’t exhibit inhibitory effects on this enzyme. It means that they may have no cardiotoxicity. Also, new targets and mechanisms of action for cardiac glycosides against cancers are existent. Meanwhile, previous studies showed that sugar chain substitution at C-3 position of cardiac glycosides was very important for their induction of Nur77 expression and anticancer effects. Changes of sugar type led to remarkable effects on their bioactivities. Based on previous studies, this project will modify the sugar chain substitution of cardiac glycosides systematically based on their skeleton and structural characteristics. The purpose of this study is to reveal their structure basis of anticancer by evaluating their anticancer effects and cardiotoxicity. Moreover, optimized bioactive compounds will be selected and labeled with biotin. Then, activity-based protein profile technology will be applied to fishing the binding targets of cardiac glycosides. Also, the exact mechanisms underlying their induction of apoptosis of cardiac glycosides will be fully elucidated. This study will establish solid foundation for searching for new cardiac glycoside anticancer drugs with high efficiency and low side effects.