土木香中与顺铂相互作用增加卵巢癌耐药细胞敏感性的不饱和内酯类成分及调控信号通路研究

肿瘤对顺铂耐药是临床化疗亟待解决的难题。申请者发现土木香中不饱和内酯类成分，在对细胞生长没有影响的剂量下，能逆转卵巢癌对顺铂的耐药作用；与顺铂合用可调控卵巢癌耐药细胞Akt、p38磷酸化水平及NF-kB等的表达。基于这类成分新的活性及解决肿瘤对顺铂耐药的迫切需求，本项目拟采用现代色谱分离技术，从土木香中获得多种具有逆转卵巢癌对顺铂耐药作用的不饱和内酯类成分，研究该类成分调控耐药细胞环境以及与顺铂的相互作用、调控PI3K/Akt及MAPK信号通路与细胞凋亡的关系，探讨不饱和内酯类化合物增加耐药细胞对顺铂敏感性的分子机制，揭示该类化合物如何与顺铂相互作用和调控的关键信号分子，并采用裸鼠模型确证该类化合物逆转卵巢癌对顺铂的耐药作用和涉及的主要信号通路。该研究为克服卵巢癌耐药提供重要的理论和实验依据，为寻找高效低毒的肿瘤顺铂耐药逆转剂开辟新途径。

Cisplatin-resistance is a major hurdle in cancer chemotherapy. There is an urgent need to find an effective approach to overcome tumor resistance. We have recently found that the unsaturated lactones from Inula helenium may overcome the resistance of ovarian cancer cells to cisplatin at the low dose, at which the unsaturated lactone alone did not cause cell growth inhibition. Our previous study showed that the combinations of cisplatin with the unsaturated lactones such as alantolactone regulated the levels of phosphorylated Akt, phosphorylated p38 and NF-κB expression. Based on these findings, we will isolate a large number of the unsaturated-lactones from Inula helenium, test the potential of these compounds to sensitize cisplatin-resistant human ovarian cancer cells to cisplatin-induced cell death, and investigate the underlying mechanism. To reveal the critical signaling molecules regulated by the combinations of cisplatin and active compounds and elucidate the mechanism of synergetic effect, the cell microenvironment such as redox status and multiple signaling pathways including PI3K/Akt, MAPK and apoptosis pathway will be investigated. Furthermore, we will determine the synergetic effect on the inhibition of tumor xenograft growth and the changes of critical signaling molecules in vivo. This study will elucidate mechanism of synergetic effect on cisplatin-resistant ovarian cancer treated by the combinations of cisplatin with the unsaturated lactones. Successful completion of the proposed study will provide a novel strategy for developing new drug with a low toxicity to overcome tumor resistance to cisplatin.