基于代谢重编程“静态-动态”多组学表征的温莪术榄香烯部位抗前列腺癌作用机制研究

从温莪术挥发油中制备的榄香烯部位（含β-榄香烯约80%）具有广谱抗肿瘤、联合放化疗增效减毒和逆转耐药的作用，但分子机制尚不明确。新近研究表明肿瘤代谢重编程是支持肿瘤细胞快速增殖及形成放化疗抗性的关键。我们近期发现榄香烯部位可明显抑杀前列腺癌（PC）细胞，活性优于β-榄香烯，且能调控其“糖-脂”等代谢重编程，提示榄香烯部位具有潜在的多成分整合抗PC作用，靶向代谢重编程可能是其重要作用机制。本项目拟建立整合指数法明确榄香烯部位多成分抗PC的整合作用；构建基于代谢重编程“静态-动态”多组学表征技术发现榄香烯部位靶向PC代谢的蛋白和代谢通路、分子探针技术发现其直接作用靶点，经综合分析明确榄香烯部位多成分靶向PC代谢重编程的分子机制；最后采用裸鼠PC模型验证榄香烯部位抗PC活性和作用机制。所得结果不仅为榄香烯治疗PC及联合放化疗治疗肿瘤提供理论依据，也能促进靶向肿瘤代谢重编程的创新中药研究。

Elemene extract (containing about 80% β-elemene), prepared from the essential oil of the rhizomes of Curcuma wenyujin, has a broad spectrum of anti-cancer activity and synergistic effect with radiotherapy and chemotherapy, and also possess the reversal effect of multidrug resistance. However, the mechanism of action of the elemene extract for cancer treatment is not yet clear. Recent studies have demonstrated that the metabolic reprogramming of cancer cells plays pivotal roles in the regulation of nutrient metabolism to support their proliferation and produce resistance for radiotherapy and chemotherapy. Most recently, we found that the elemene extract could obviously inhibit the growth of prostate cancer (PC) cell line, PC3 cells, and the inhibitory activity is better than that of β-elemene. Further study revealed that the elemene extract could regulate the Warburg effect and fatty acid synthesis metabolism of PC3 cells. We therefore reasoned that regulating the metabolic reprogramming using a “multi-compounds vs multi-targets” manner is the important mechanism of action of elemene extract against PC. In this program, we sought to test this hypothesis. Firstly, we plan to use the combined index to study the synergistic, additive or antagonistic effect of the bioactive compounds in elemene extract against PC. Then, we plan to develop a new strategy based on “static-dynamic” multi-omics profiling of metabolic reprogramming to discover the targeting pathways (protein and metabolism) of the elemene extract. Meanwhile, the molecular probes of the bioactive compounds in elemene extract will be synthesized to find the binding targets of the bioactive compounds. Afterward, we will analyze comprehensively the targeting pathways and binding targets to figure out the molecular mechanism of the bioactive compounds targeting the metabolic reprogramming of PC. Finally, the verification of anti-PC activities and mechanism of action of the elemene extract will be accomplished in the PC-bearing nude mouse models. The results of this program could not only provide a theoretical basis for the application of elemene on the clinical treatment of PC and for the cancer treatment by combining elemene with radiotherapy and chemotherapy, but also promote the research of innovative traditional Chinese medicines that targeting the cancer metabolic reprogramming.