在癌症的放化疗中适当地使用DDR（DNA损伤应答）抑制剂可以增强癌细胞对放化疗的敏感性，从而提高癌症病人的生存机会。前期我们从牛角瓜(Calotropis gigantea)的茎叶中分离得到3个新的和11个已知的强心苷类化合物，并发现它们对肿瘤细胞的增殖有不同程度的抑制作用，其中化合物coroglaucigenin对X-射线诱导的肺癌细胞DNA损伤的修复过程具有延缓作用。本课题拟集成波谱筛选和生物活性跟踪技术，深入挖掘牛角瓜属两种植物中强心苷类活性分子，并对量大的化合物进行结构修饰，进而评价系列强心苷类分子的细胞毒活性，对活性较好的分子进行DNA损伤修复方面的研究，探讨其对DDR通路的影响，明确具有DDR抑制活性的强心苷类分子的作用功效与机制。该研究有望使天然产物在癌症治疗作用中有新突破；也将为这类具有强心作用、临床上主要用以治疗慢性心功能不全的“强心苷类化合物”找到新的应用价值。

DDR (DNA damage response) inhibitors could make cancer cells more sensitive to the effects of radiotherapy/chemotherapy. Combination of DDR inhibitors with radiotherapy/chemotherapy is viable for the clinical treatment of cancers and could enhance the survival rate. In our previous study, three new cardenolides along with 11 known ones were isolated from the leaves of Calotropis gigantea. All of the isolates were evaluated for cytotoxic activity against cancer cell lines, and all cardenolides tested were found to possess different inhibitory effects from strong to weak. Moreover, pretreatment with coroglaucigenin can delay and inhibit DNA damage repair induced by X-rays in cancer cells. In this project, we will further investigate the cardenolides from Calotropis genus by integrated application of spectral and bioactive screen. Subsequently, the structures modifications of compounds will be carried out. For the discovery of the bioactive compounds with high efficiency and low toxicity, the cytotoxic activities about the isolated and semisynthetic cardenolides will be implemented. From the above results, we expect to obtain some promising lead compounds with DDR inhibited activity and then implement the study of the molecular mechanism. This project, including our previous results and the coming research, will not only lead to the new breakthrough of natural compounds used in cancer therapy, but also have new application value for cardenolides, a class of steroid-like compounds, that are well appreciated in the treatment of congestive heart failure and arrhythmia.