基于LIF 信号通路探讨石蒜中生物碱类抗肝癌药效物质基础及作用机制

Hepatocellular carcinoma has a poor prognosis with high degree of malignancy, there is currently no effective treatment. Lycoris Radiata Herb (LRH) possesses qufengxiaozhong, jiedu effect according to Traditional Chinese Medicine (TCM) theory and is potentially used to treat hepatocellular carcinoma, but the material basis and mechanism of action is not clear. In our previous studies, alkaloids compounds from LRH were isolated and identified. It was found that administration of Lycorine can decrease leukemia inhibitory factor (LIF) protein expression, inhibite cell proliferation, promote apoptosis and inhibit PMA-regulated invasion and migration in human hepatocellular carcinoma cells. We also found that exogenous LIF expression could block Lycorine-regulated anti-cancer activity in HepG2 cells. This project intends to systematicly investigate the chemical constituents from LRH, test anti-proliferation effect, evaluate their pharmacodynamics in vivo and in vitro, and clarify the various potential signaling pathway and molecular mechanisms of anti-cancer activity (apoptosis, invasion and migration, proliferation). We will explore the efficacy of anti-tumor traditional Chinese medicines LRH; the scientific hypothecs that LRH could regulate apoptosis and migration in human hepatocellular carcinoma cells by LIF pathways to exert the effect on the anti-cancer joints was verified. This program intends to clarity the material basis, apoptosis and migration mechanism of action and provide adequate scientific basis for molecular target drug of LIF and its preparation.

肝癌恶性程度高、且预后差，目前尚无有效的治疗手段。中药石蒜有祛风消肿、解毒之功效，研究表明石蒜具有潜在的抗肝癌作用，但物质基础及作用机理尚不明确。本课题前期对石蒜中部分生物碱类成分进行活性追踪，发现其中的石蒜碱可以降低肝癌细胞中白血病抑制因子（LIF）的蛋白表达，并具有诱导凋亡，抑制增殖、迁移及侵袭的抗肝癌活性，同时发现外源性LIF 可以显著阻断石蒜碱的抗肝癌作用。本项目拟对石蒜中生物碱类进行系统的化学成分研究，通过活性筛选及体内外药效学评价，确定其活性成分，并阐明抗肝癌（凋亡、迁移及侵袭、增殖）信号通路及分子作用机制，探讨中药石蒜生物碱抗肝癌药效物质基础，验证“中药石蒜生物碱通过LIF 介导的途径调节肝癌细胞凋亡及其转移机制发挥抗肿瘤作用”科学假说。本研究拟阐明石蒜抗肝癌的药效物质及分子作用机制，为作用于LIF 的新型抗肝癌分子靶向药物的研发提供科学依据。

肝癌是各类癌症细胞中恶性程度极高、且预后最差的一类，俗称“癌中之王”，目前尚无有效的治疗手段。中药石蒜具有解毒、祛痰、利尿、催吐等多种功效，主要用于治疗咽喉肿痛、痈肿疮毒、瘰疬、水肿等。本课题围绕石蒜中主要活性成分生物碱类进行系统的化学成分研究，分离得到15个生物碱类化合物，并鉴定了其化学结构。通过体外活性筛选及体内外药效学评价，发现石蒜碱和7-去氧水仙环素具有较好的抗肝癌活性，利用细胞生物学、分子生物学、网络药理学、肿瘤学等多学科交叉融合，阐明其抗肝癌药效物质基础及分子作用机制。验证“石蒜生物碱类通过LIF相关信号通路介导肝癌细胞凋亡及其转移机制发挥抗肿瘤作用”科学假说，为抗肿瘤分子靶向药物的研发提供科学依据。以第一或通讯作者发表SCI论文6篇（3篇五年平均IF＞5）；申请发明专利6项。先后获得天津市“青年科技优秀人才”，天津市 “优秀博士后国际化培养计划”，中华中医药学会“中青年创新人才”，天津市高校“中青年骨干创新人才培养计划”。