针对肿瘤细胞能量代谢网络的中药抗肿瘤靶标系统的研究

Generally, traditional Chinese medicine (TCM) still plays a subordinate role to chemotherapy as an anticancer therapy. To fully realize TCM's anticancer potential and make breakthroughs in cancer treatments by TCM, it's necessary to develop new strategies and methods for the discovery of novel anticancer TCMs. In this project, we propose a new concept of energy metabolism networks of cancer cells (EMNCC) and hypothesize that correcting or destroying the EMNCC can produce significant anticancer effect. This project has two specific aims. Aim 1: To establish a target system that correct or destroy the EMNCC for the discovery of novel anticancer TCMs. We will investigate the anticancer effect and the mechanism of action by modulating the EMNCC using the gene silencing method combined with small molecular probes to target several key enzymes of the EMNCC. Aim 2: To study the effects of bioactive ingredients and the commonly used TCMs used for cancer treatments on the EMNCC to discover their own target enzymes. The results from this study will guide the use of the combined TCMs or combined bioactive ingredients to produce anticancer complex Chinese patent medicines or medicines based on multiple bioactive ingredients, which will provide a foundation for the discovery and development of novel anticancer TCMs. Given that the EMNCC plays a pivotal role in the process of tumorigenesis, tumor progression, and drug resistance, the target system established in this project will not only target this pivotal role, but also conform to the special characteristics of TCMs that treat diseases systemically through multiple targets and multiple bioactive ingredients. Therefore, this target system is expected to optimize and integrate the abundant resources of the anticancer TCMs with great improvement of their efficacy.

中医药治疗肿瘤总体来说还处于辅助地位,要充分发挥其抗肿瘤潜力、取得新的突破，中药抗肿瘤研究需要采用新策略、新方法。本课题首次提出肿瘤能量代谢网络的概念，认为纠正或破坏此代谢网络可产生显著的抗肿瘤作用。所以，该研究首先要建立一种纠正或破坏肿瘤能量代谢网络的抗肿瘤药物靶标系统，为此用基因沉默方法并结合小分子探针靶向此网络的多个关键酶，研究纠正或破坏此网络的抗肿瘤作用及其机制；而后研究抗肿瘤中药活性成分和常用中药制剂对肿瘤能量代谢网络的作用并发现各自的靶标酶。研究结果可指导中药或其有效成分配伍联用，组建纠正或破坏肿瘤能量代谢网络的多靶点抗肿瘤的中药或其有效成分复方，为研发具有显著抗肿瘤作用的创新中药奠定基础。本课题拟建立的抗肿瘤药物靶标系统既抓住了肿瘤发生发展和肿瘤耐药的关键环节，又符合中医药多靶点、系统治疗的特色，可使广泛的中医药抗肿瘤资源得到优化和整合，预期可显著提高中医药治疗肿瘤的效果。

本课题围绕核心目标——拟阐明破坏肿瘤代谢网络的抗肿瘤意义及其靶标酶, 为研究与开发治疗肿瘤的多靶点创新中药奠定基础，为中药抗肿瘤机制研究提供新方法、新思路——建立了用C13 标记联用LC-MS追踪葡萄糖和谷氨酰胺分别流向能量代谢通路和生物合成通路的技术平台，阐明了促进氧化磷酸化并阻断多条生物合成通路对抗肿瘤的重要意义，提出一种以LDH5，TKTL1，SHMT1和FASN 等为靶点来破坏肿瘤代谢网络的策略。此外，阐明了能量代谢调控剂ZZZ-1可全面逆转肿瘤代谢特征，促进线粒体氧化磷酸化并关闭各种关键生物合成代谢通路，对胶质瘤细胞具有显著的体内外杀伤作用。具有广谱抗癌活性的中药活性物质CADPE也可广泛逆转肠癌细胞的能量代谢特征，对各种异质肠癌细胞具有显著的体内外抗癌活性。这两种化合物均具有良好的转化应用前景。