黄芩汤抑制鼻咽癌胸苷酸合成酶的机制研究

Nasopharyngeal carcinoma originated from epithelial cells of nasopharynx and is one of the most common carcinomas in southern China. Fluorouracil is a common drug used in nasopharyngeal cancer induction chemotherapy and plays an important anti-tumor role. However, the sensitivity of 5-FU to chemotherapy varies greatly among different patients, which limits the further clinical application of 5-FU.Therefore, to improve the sensitivity of tumor patients to 5-FU and reduce adverse drug reactions is not only one of the current hot spots in the field of anti-tumor drug research, but also an important scientific problem to be solved in clinical chemotherapy. Clinical observation shows that huangqin decoction can enhance the sensitivity of 5-FU and reduce the adverse reactions. Previous studies found that huangqin decoction significantly inhibited the protein expression of 5-FU-targeted TYMS, which was taken as a starting point to further study the mechanism of huangqin decoction in inhibiting TYMS, and LC/MS/MS combined with database was used to identify the structure of the active components of huangqin decoction. Molecular docking was used to screen the active molecules specifically bound to TYMS. Complex crystals were obtained by co-crystallization of protein-active small molecules, and the structure information of the binding of target protein and drug molecules was obtained by X-ray diffraction. In order to find out the exclusive inhibitors of thymosidic synthase and provide theoretical basis for improving the sensitivity of 5-FU chemotherapy, reducing adverse reactions and improving the overall survival rate of nasopharyngeal cancer patients.

鼻咽癌来源于鼻咽上皮细胞，是我国南方地区高发癌种之一。5-氟尿嘧啶是鼻咽癌诱导化疗的常用药物发挥了重要的抗肿瘤作用，但不同病人对5-FU的化疗敏感性具有很大差异，限制了5-FU进一步临床应用。因此提高肿瘤患者对5-FU化疗敏感性、降低不良反应，不仅是当前抗肿瘤药物研究领域的热点之一也是临床亟需解决的重大科学问题。临床研究显示黄芩汤在增强5-FU化疗敏感性、减轻不良反应方面具有一定作用。我们前期研究发现黄芩汤显著抑制5-FU靶标胸苷酸合成酶的蛋白表达。以此为切入点，深入研究黄芩汤抑制胸苷酸合成酶的机制，采用LC/MS/MS结合数据库鉴定活性成分的结构；分子对接筛选与胸苷酸合成酶特异结合的活性分子；蛋白-活性小分子共结晶，利用Ｘ射线衍射技术，获得靶蛋白与药物分子结合的结构信息。以期发现胸苷酸合成酶的专属抑制剂，为提高鼻咽癌5-FU化疗敏感性、降低不良反应，提高患者总生存率提供理论依据。

鼻咽癌来源于鼻咽上皮细胞，是我国南方地区高发癌种之一。5-氟尿嘧啶是鼻咽癌诱导化疗的常用药物发挥了重要的抗肿瘤作用，但不同病人对5-FU的化疗敏感性具有很大差异，限制了5-FU进一步临床应用。因此提高肿瘤患者对5-FU化疗敏感性、降低不良反应，不仅是当前抗肿瘤药物研究领域的热点之一也是临床亟需解决的重大科学问题。临床研究显示黄芩汤在增强5-FU化疗敏感性、减轻不良反应方面具有一定作用。我们前期研究发现黄芩汤显著抑制5-FU靶标胸苷酸合成酶的蛋白表达。本研究深入探讨了黄芩汤抑制胸苷酸合成酶的机制，采用LC/MS/MS结合数据库鉴定174种活性成分的结构；并通过分子对接筛选发现了11种与胸苷酸合成酶特异结合的活性分子；其中山楂酸结合能力和抑制活性最强。同时我们也研究了TYMS促进鼻咽癌进展的分子机制，体内外功能学研究表明，TYMS在鼻咽癌发生发展中扮演促癌基因的角色，并且上游基因VCP通过去泛素化稳定TYMS进而发挥其生物学功能。最后我们发现上游基因VCP的抑制剂联合5-FU具有提高5-FU对鼻咽癌化疗敏感性的作用。本研究为提高鼻咽癌5-FU化疗敏感性、降低不良反应，提高患者总生存率提供理论依据。