二氢丹参酮I对多药耐药结肠癌及胃肠肿瘤活化成纤维细胞中代谢重编程的调控作用及机制研究

项目名称： 二氢丹参酮I对多药耐药结肠癌及胃肠肿瘤活化成纤维细胞中代谢重编程的调控作用及机制研究

项目编号： No.81503113

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 王霖

作者单位： 中国医学科学院药物研究所

项目金额： 17.9万元

中文摘要： 瓦博格效应及“上皮基质代谢耦联”均为肿瘤代谢的重要特征，也是促使肿瘤耐药及转移的主要原因。申请者前期发现，二氢丹参酮I（dihydrotanshinone I，DHTS）具有活性氧依赖的抗结肠癌及结肠癌多药耐药活性，并对结肠癌细胞及相应荷瘤裸鼠中丙酮酸脱氢酶酶复合体激酶基因表达具有显著的抑制作用。本项目将以结肠癌多药耐药细胞株、结肠癌活化成纤维细胞（colon cancer activating fibroblasts, CAF）及相应的耐药荷瘤裸鼠模型为对象考察DHTS抗结肠癌耐药是否通过ROS/Akt/mTOR/HIF1α与PDK4/CREB/RHEB/mTORC1信号通路实现对代谢重编程的调控；建立耐药结肠癌细胞与CAF共培养模型，探讨DHTS是否通过CAF而间接调控耐药结肠癌细胞有氧糖酵解。本项目研究成果将为DHTS的结构优化及基于代谢调控的肿瘤治疗佐剂开发提供重要理论基础。

中文关键词： 结肠癌；二氢丹参酮I；有氧糖酵解；活性氧；线粒体

英文摘要： “Warberg effect” and “Epithelial stromal metabolic coupling” are two typical characteristics of tumor metabolic reprogramming. In our previous work, dihydrotanshinone I (DHTS) was found potent reactive oxygen stress (ROS) dependent anti-colon cancer activity and efficient reverse of multi-drug resistance (MDR) in colon cancer cells. Especially, DHTS significantly decreased mRNA expression of Pyruvate dehydrogenase enzyme complex kinase (PDK) both in HCT116 cells and xenograft tumor in nude mice. In this project, we will investigate the regulation of tumor metabolic reprogramming by DHTS on several multi-drug resistant colon cancer cell and xenograft tumor developed by inoculating MDR colon cancer cells subcutaneously into NOD/SCID mice. The regulation of signaling pathways of ROS/Akt/mTOR/HIF1α and PDK4/CREB/RHEB/mTORC1 by DHTS will be studied for the reverse of metabolic reprogramming in MDR colon cancer. In addition, co-culture model of CAF and MDR colon cancer cells in Transwell will be established to evaluate the reversion of drug resistance by DHTS through CAF in MDR colon cancer cells. This study will offer important theoretical basis for the development of cancer adjuvant based on metabolism regulation and valuable information for the structure optimization of DHTS.

英文关键词： colon cancer;dihydrotanshinoneI;aerobic glycolysis ;reactive oxygen;mitochondria