基于罕见骨架结构的天然查尔酮类衍生物微管抑制剂MIL-28抗微管靶点及抗耐药机制研究

微管为靶点抗肿瘤药物是临床最有效的药物，但骨髓抑制、多药耐药副作用极大限制其疗效和应用，寻找以微管为靶点的新结构的高效抗耐药微管抑制剂是研究热点。MIL-28是我们从厚果崖豆藤中首次发现并经结构修饰获得的新型苯并吡喃查尔酮微管解聚剂，该化合物对二十种人肿瘤细胞有很强活性，其IC50 在0.05～0.5μM之间，其抑制微管聚合能力优于秋水仙素，且对多个耐药肿瘤细胞株的IC50在nM级,且非MDR底物，显示良好的抗耐药活性。体内药效学证明同等剂量MIL-28对肝癌、肺癌、结肠癌抗肿瘤效果优于紫杉醇，但毒性远小于紫杉醇，具有良好成药性，已申请国内及国际PCT专利。但是MIL-28 与现有抗微管药物结合方式不同，其作用微管具体位点和靶点还不清楚，其抗耐药机制需深入研究。本课题将利用亲和色谱、基因芯片、免疫共沉淀等技术确定其结合微管具体位点和靶点，全面解析其诱导耐药细胞凋亡、抗耐药机制。

Microtubule-targeting antitumor drugs such as paclitaxel, vinca alkaloids and taxoids are well-known examples of antimitotic agents that are widely used clinically to treat different cancers. However，their side effcts including bone marrow depression and multi-drug resistance restrict the clinical benefit and decrease the life quality of patients. New inhibitor of microtubule assembly against multi-drug resistance but with few side effects discovered from numerous small natural and synthetic molecules represents an attractive hotspot. MIL-28 is a natural pyranochalcones derivative isolated from Millettia ferruginea( Jixueteng in Chinese). This compound had a broad cytotoxic activity in several tumor cell lines with IC50 values between 0.05～0.5μM. It also showed superior inhibitory effect on tubulin polymerization to colchicine. Importantly， MIL-28 showed good inhibitory effects on drug-resistance tumor cell lines including A2780CP and MCF-7/T with IC50 values of 0.1μM and 0.6μM，respectively. In vivo study, MIL-28 significnalty inhibited the tumor growth and prolonged the life span of mice in several tumor-bearing nude mice models including liver HepG2-bearing tumor and A549-bearing tumor mice models. In this project, the aim of this study is to exploring the mechanism of MIL-28 on polymerization assembly and anticancer drug resistance.