千斤拔抗癌活性先导化合物及其作用机制

Primary lung bronchogenic carcinoma is the leading cause of mortality in oncology, with 75~80% of the cases are non-small cell lung cancer (NSCLC). FP-1, a new compound isolated from South China native herbal medicine Flemingia philippinensis, is a unique anti-cancer compound which showed noticeable autophagic cell death inducing activity towards non-small cell lung cancer cell A549 with an IC50 value ranging within 1-5 μM, with minor contribution from apoptosis. The current proposal aims to investigate the proliferation inhibitory effect and the mechanisms of action of FP-1 inducing A549 cell death which may provide experimental basis for developing new anticancer drug used in Non-small cell lung cancer clinical treatment with more favorable efficacy/side effects profile. New lead compound search and structure optimization will also carried out from screening a compound library composed of natural prenylated isoflavonoids, natural ones with structure modification and synthetic analogs on the basis of Structure-Activity-Relationship (SAR) analysis, which will benefit new anticancer drug discovery program by providing promising optimized lead compounds and drug candidates.

肺癌是全球发病率及死亡率最高的恶性肿瘤。从天然产物中寻找新结构和新作用机制的高效低毒抗癌药物是当前癌症研究的热点。FP-1是从岭南特色中药千斤拔（F. philippinensis）中分离鉴定的一个新结构异黄酮类成分，对人体肺癌细胞A549的增殖有明显抑制活性（IC50 2.4 μM）。我们的前期研究发现FP-1主要通过"自噬"来抑制癌细胞增殖，是一个独特的抗癌先导化合物。本项目拟对FP-1的抗癌作用机理作深入研究，揭示其对A549细胞自噬的诱导和调控机制，阐明其凋亡与自噬的相互作用（拮抗vs协同），为"自噬"类抗癌药物的研发提供药理学理论依据。同时，在大量筛选FP-1同系物（包括从植物提取和合成半合成的衍生物）和构效关系（SAR）分析基础上，对多异戊烯基取代的植物异黄酮类进行结构改造和优化，获取活性更强、特异性更好的异黄酮类抗癌化合物，为高药效低毒抗癌新药的研发提供药物先导化合物。

本项目系统研究了千斤拔、桃金娘、米碎花、鸦胆子等6种岭南特色植物中的抗癌活性天然产物，从中分离鉴定出150多个化合物，其中新骨架3个，新化合物有25个。通过对多种癌细胞株的抑制活性筛选，发现蔓性千斤拔素G等4个化合物具有强烈抑制癌细胞增殖的活性，还有其它26多个化合物具有不同程度的抑制活性，并确定A549非小细胞肺癌细胞、MCF-7乳腺癌细胞等为敏感癌细胞株；针对最敏感的A549肺癌细胞，发现蔓性千斤拔素G主要是通过诱导癌细胞自噬而引起癌细胞死亡，进一步明确其抑癌作用机理。本项目已发表8篇论文、培养4名硕士生，超额完成预定指标。

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