肿瘤代谢多靶标策略的海洋微生物新型抗胶质瘤先导化合物的发现及生物活性的研究

Gliomas remain the most common and lethal brain tumors. Therefore, there is an urgent clinical need to discover and develop novel anti-glioma drugs. Tumor cell metabolic reprogramming provides new targets for gliomas therapy. The discovery and development of small molecular antitumor agents through the manipulation of single molecular target or pathway of tumor metabolism have not made anticipated breakthroughs so far. Our preliminary studies indicated that the regulation of multiple glioma metabolic enzymes, biological small molecules, and oncogenes by several natural compounds produced potent anti-glioma activity with low toxicity, suggesting the scientific significance and application prospect of the modulation of multiple targets of tumor metabolism for the discovery of novel anti-glioma agents. This proposal has three specific aims. Aim I: To develop a new method by targeting several metabolic regulators of key enzymes, biological small molecules, and oncogenes, which are related to the tumorigenesis of gliomas, for the discovery and study of anti-glioma agents. Aim II: To discover novel anti-glioma compounds from cultures of marine microorganisms obtained from the prophase study, which produced anti-glioma metabolites targeting the tumor metabolism. Aim III: To intensively investigate the anti-glioma effects and mechanisms of action of the representative anti-glioma compounds, including four novel ones from marine actinomycetes in our previous investigation for this study. This study will open a new window for the discovery and study of novel anti-glioma agents by targeting multiple regulators of tumor metabolism and provide lead compounds, even candidate drugs, for the development of novel anti-glioma drugs.

胶质瘤是最常见和最致命的脑肿瘤，临床迫切需要抗胶质瘤新药物。肿瘤细胞特征性代谢为胶质瘤的治疗提供了新靶标。目前靶向肿瘤代谢某单一靶标或信号通路的小分子抗肿瘤药的研究未取得期待的突破。前期研究发现，数个天然小分子干预肿瘤不同代谢途径的特异关键酶、生物小分子和癌基因，具有抗胶质瘤活性强和毒性低的特点，提示多靶标调控肿瘤代谢研究发现抗胶质瘤活性物质的研究意义和应用前景。本项目以胶质瘤细胞代谢所偏爱依赖的数个特异关键酶、生物小分子和癌基因为靶标，构建多靶标研究发现抗胶质瘤活性物质的新方法，从前期研究已获得的海洋放线菌(影响肿瘤代谢的活性物质的产生菌)中发现新的抗胶质瘤活性物质，深入研究代表性活性化合物(包括前期研究已获得的四个)的抗胶质瘤生物活性，阐述该研究方法的科学性和应用价值。本项目将为肿瘤代谢多靶标抗胶质瘤活性物质的研究开辟新途径，为新型抗胶质瘤药物的研究提供先导化合物甚至候选药物。

海洋微生物是发现新型抗肿瘤活性天然产物和药物先导化合物的重要资源。本项目首先从来自浙江舟山的东海海域、印度尼西亚的太平洋海域、巴基斯坦的阿拉伯海域和马里亚纳海沟等地的海洋生物、海泥和海底沉积物等不同样品中分离得到了800多株海洋微生物，包括330株马里亚纳海沟深渊微生物，发现了128株菌培养物的提取物具有抑制胶质瘤细胞增殖的活性。然后，选择其中32株菌进行了扩大培养，从这些菌株的培养物中分离鉴定了450多个代谢产物，发现了135个新化合物，包括13个新骨架结构化合物、41个稀有化合物和40多个具有抑制胶质瘤细胞增殖活性的新化合物，其中14个为高活性的新化合物。最后，对8个代表性的高活性化合物的毒性、血脑屏障透过性、在血浆中的稳定性和抗肿瘤作用及机制进行评估，发现pyrrospirone G和streptoglutarimide H是理想的抗胶质瘤侯选药物，具有进一步深入研究的应用价值。本项目的研究发现已在国际主流的SCI学术期刊发表了研究论文30，获得10项授权发明专利。本研究不仅为新型抗胶质瘤药的研发提供了两个药效分子，而且证明了基于靶向肿瘤代谢多靶标策略从海洋微生物代谢产物中发现新型抗胶质瘤活性物质和药物先导化合物的应用前景。