基于肿瘤模式动物的菝葜酚酸物质抗癌活性成分及先导化合物结构修饰研究

Smilax china L，known as "Jin Gang Teng", is a traditional Chinese medicine listed in Chinese pharmacopoeia in 2010. It is frequently used for promoting diuresis,expelling phlegm, and treating cancer in China. In previous studies, we identified a phenolic acid compound pool purified from Smilax china L which exhibits the best potency against tumorigenesis. Using multi-crossed displinary approaches including those from modern pharmacy, pharmacology, molecular and cellular biology, metabonomics, animal modeling, etc, the current proposal aims at 1) systematic evaluation of these phenolic acid compounds respectively in in-vitro cultured tumor cells; 2) profiling the fingerprints of the phenolic acid pool and the potential metabolites in in-vivo tumors; 3) screening candidates with strongest tumor suppressing activities in combination of results from aim 1 and aim 2; 4) pharmacokinetic study and structure modification of the identified compounds; and 5) mechanistic investigation of the identified compounds in regulation of apoptosis and tumor angiogenesis both in vitro and in vivo.The final goals of our research are aimed to 1) identify compounds with strongest tumor suppressing activities; 2) provide lead compounds for developing anti-cancer drugs; 3) probe the molecualr targets of the identified compounds; and finally build up a solid and rational basis for future application of Smilax china L in target-based cancer therapy.

菝葜（Smilax China L）的药材名乃金刚藤，为传统中药，收载于2010年版《中国药典》一部，具有祛痰利湿、解毒散瘀的功效，是中医临床用于治疗肿瘤疾患的常用中药。项目组前期研究发现，菝葜抗肿瘤主要有效物质为酚酸类成分。本申请项目拟在前期研究基础上，以菝葜酚酸类成分标准提取物为研究对象，通过"肿瘤模式动物"的体内过程，采用现代色谱、波谱技术，分析和鉴定含药肿瘤组织的原型成分和代谢产物；并与体外分离、筛选的抗肿瘤活性成分比对分析，准确界定菝葜抗肿瘤有效成分；然后采用国际先进实验方法，对有效成分进行抗癌作用机理和药动学研究，探讨其抗癌途径及体内代谢规律；选择高活性有效成分作为先导化合物，进行化学结构修饰研究，在药理筛选跟踪下优选最佳活性目标化合物。本项目预期研究成果可望充分诠释菝葜抗肿瘤的物质基础，探讨中药抗肿瘤有效成分研究的新途径，为研制抗肿瘤创新药物提供科学依据。

本项目在前期研究基础上，以系统分离的菝葜提取物为研究对象，通过体外系统和体内模型相结合，筛选菝葜的抗肿瘤有效成分，研究其抗癌的分子机制。研究以来源不同的肺癌细胞株为模型，利用PI-Annexin V staining，分析不同提取成分诱导体外培养的肺癌细胞凋亡的情况。相关研究结果《菝葜体外抗非小细胞肺癌细胞活性物质研究》一文已被《中国现代中药》杂志（刊号：CN 11-5442/R ISSN 1673-4890）录用，拟安排在近期刊登。目前正利用小鼠模式动物，进一步研究相关提取物的体内作用机制，相关研究结果预期2014发表。