五味子乙素靶向MyD88逆转胃癌卡培他滨耐药的活性和机制研究

Schisandrin B，a nontoxic extraction of Chinese traditional medicine, can serve as chemosesitizer and organ-protection agents, and possesses the capability of anti-inflammation, anti-oxidation and anti-tumor. But the ambiguous targets limited its application. Our previous studies demonstrated schisandrin B attached to MyD88 via molecular docking and could improve the sensitivity and reverse the resistance of gastric cancer (GC) to capecitabine. We hypothesize Myd88 highly express in gastric cancer and mediate its chemotherapy resistance, while schisandrin B can reverse the resistance of gastric cancer to capecitabine by targeting to MyD88. In this program, we will confirm schisandrin B targeting to MyD88 and reverse the desensitization of capecitabine through cell lines, primary cells and molecular biology levels, using gastric cancer xenografts and spontaneous tumor models. Then, we will investigate the specific mechanism of drug resistance mediated by MyD88 through lentiviral silencing and plasmid high expression techniques and explore the relationship between the expression level of MyD88 and the prognosis as well as resistance of GC patients. This activity and mechanism study based on the sensitization and reversion of schisandrin B to GC by targeting to MyD88 will provide new ideas in the combination of traditional Chinese medicine and cytotoxic drugs for chemotherapy.

五味子乙素是一种无毒、且能作为化疗增敏剂、器官保护剂使用的中药提取物，具有抗炎、抗氧化、抗肿瘤活性，但靶点不明确限制其用途。本课题组前期通过分子对接发现五味子乙素能结合MyD88，并能增加卡培他滨敏感性，逆转胃癌对卡培他滨的耐药。据此我们提出假设：Myd88在胃癌中表达上调并介导胃癌化疗耐药；五味子乙素能靶向MyD88，逆转胃癌细胞对卡培他滨的耐药。本项目将从细胞系、原代细胞、分子水平、皮下移植瘤和肿瘤自发模型确证五味子乙素通过靶向MyD88逆转卡培他滨耐药，并通过慢病毒沉默、质粒高表达研究MyD88介导耐药的具体机制，临床水平探讨分析胃癌MyD88表达水平与胃癌患者预后及耐药的关系。研究基于五味子乙素靶向MyD88对胃癌化疗增敏和逆转耐药的活性和机制，为中药联合细胞毒类药物化疗提供新的思路。

五味子乙素是一种无毒、且能作为化疗增敏剂、器官保护剂使用的中药提取物，具有抗炎、抗氧化、抗肿瘤活性，但其机制和靶点不明确，限制了其用途。本项目发现五味子乙素能够与MyD88有效结合，抑制胃癌细胞中MyD88下游信号通路STAT3的磷酸化激活，抑制Beclin-1、P62、LC3的表达。五味子乙素在体外具有较好的抗胃癌活性；与前体药物卡培他滨的有效成分5-FU联用后，能够有效增强5-FU抑制胃癌细胞生长和集落形成的活性；在5-FU耐药株中，也能有效逆转胃癌5-FU耐药。在裸小鼠的胃癌细胞异种移植瘤中，五味子乙素与5-FU联合，能够有效增强5-FU的体内抗胃癌活性。在裸小鼠的5-FU耐药胃癌细胞异种移植瘤中，五味子乙素和5-FU单药仅有很弱的抗体内胃癌生长作用，但五味子乙素和5-FU联用后，体内抗胃癌活性大幅增加，即五味子乙素在体内能够有效逆转胃癌5-FU耐药。本项目也发现五味子乙素衍生物五味子丙素具有较好的抗胃癌及增敏胃癌化疗活性。总之，本项目为胃癌化疗提供了候选新药，为五味子乙素提供了新靶点和新用途，也为五味子丙素增加了新的药用价值。