基于肿瘤内皮细胞代谢的参麦方调控肿瘤血管生成的药代动力学物质基础及机制研究

Shenmai Formula is one of the famous Traditional Chinese medicine preparations in our country, which has a significant effect on cardiovascular diseases, and can be used in the adjuvant therapy of tumor. Our previous study found that Shenmai injection significantly inhibited tumor angiogenesis in patients with colon cancer and mouse model, and had significant effects on endogenous metabolism in tumor tissue especially the fatty acid metabolism pathway. This project will track the active ingredients in Shenmai Formula based on the "plasma→tissues→target cells" multi-level pharmacokinetics technology, clarify the metabolism, elimination and composition changes of its active ingredients in the target tissue/cells, then investigate its correlation with tumor angiogenesis. Based on the hot research on targeting energy metabolism in vessel endothelial cells for inhibiting pathological angiogenesis, we will separate tumor endothelial cells and establish its metabonomics research methods. Combined with the component-knockout approach, try to find the active components for the anti-angiogenesis effect and the endogenous metabolism regulation in tumor endothelial cells. Try to find the correlation of pharmacokinetics and pharmacodynamics of Shenmai active ingredients from the point of endogenous metabolism regulation in tumor endothelial cells, and clarify the material basis of Shenmai Formula for anti-angiogenesis in tumor. The evaluation for pharmacological effect of the active components which targeting the tumor endothelial cells will be performed, followed by the optimization of the proportion of the active ingredients, which can provide the basis for the clinical use of Shenmai Formula in anti-angiogenesis in tumor therapy.

参麦方是我国的经典名方之一，临床对心血管疾病效果显著，且可用于肿瘤辅助治疗。申请者前期研究发现在结肠癌患者和小鼠模型上参麦注射液均显著抑制肿瘤微血管的异常增生，且对肿瘤组织中内源性代谢特别是脂肪酸代谢通路有显著影响。本项目拟基于“血浆→组织→靶细胞”多水平药代动力学研究技术对参麦方进行活性成分群追踪，阐明其活性成分群在靶组织/细胞的代谢消除、成分构成比改变的规律，及其与抗肿瘤血管生成的相关性；针对血管内皮细胞能量代谢调控治疗病理性血管生成的研究热点，分离并建立肿瘤内皮细胞代谢组学研究方法，结合参麦方组分剔除法寻找其抗肿瘤血管生成及调节肿瘤内皮细胞代谢的活性组分；以肿瘤内皮细胞代谢为切入点对参麦方活性成分的药动、药效进行关联研究，阐明参麦方中通过调节肿瘤内皮细胞代谢发挥抗肿瘤血管生成的药效物质基础；进行靶向内皮细胞的活性组分药效验证及配比优化，为参麦方用于临床抗肿瘤血管生成治疗提供依据。

参麦方是我国的经典名方之一，临床对心血管疾病效果显著，且可用于肿瘤辅助治疗。但其对于肿瘤化疗增效作用的物质基础及机制并不清晰。在前期研究发现参麦注射液在结肠癌患者和小鼠模型上均显著抑制肿瘤微血管异常增生的基础上，本项目基于“血浆→组织→靶细胞”多水平药代动力学研究技术对参麦方进行活性成分群追踪，阐明其活性成分群在靶组织/细胞的代谢消除、成分构成比改变的规律，及其与抗肿瘤血管生成的相关性。研究发现二醇型人参皂苷在肿瘤血管内皮细胞中累积量较高，其中Rd最高，其可能是靶向调节肿瘤血管内皮细胞发挥抗肿瘤血管生成作用的重要活性成分。并且通过试验排除了三醇型人参皂苷、麦冬对肿瘤血管的作用。进一步针对血管内皮细胞能量代谢调控治疗病理性血管生成的研究热点，分离并建立肿瘤内皮细胞代谢组学研究方法，寻找其抗肿瘤血管生成及调节肿瘤内皮细胞代谢的重要环节及机制。代谢组学及分子生物学研究显示肿瘤血管新生时内皮细胞的脂肪酸氧化及乙酰辅酶A代谢通路显著增强，给予参麦注射液和Rd可以显著抑制脂肪酸氧化、乙酰辅酶A代谢通路及其关键酶ACLY，从而抑制了肿瘤血管内皮细胞的组蛋白H3乙酰化，及其下游基因的转录。. 本研究以肿瘤内皮细胞代谢为切入点，通过多维度和靶细胞药代动力学阐明了参麦方中二醇型人参皂苷特别是Rd可能是调节肿瘤内皮细胞代谢发挥抗肿瘤血管生成的药效物质基础，为参麦方用于临床抗肿瘤血管生成治疗提供了依据；同时提出靶向肿瘤血管内皮细胞代谢及天然活性组分的药物发现为肿瘤血管的调控提供了新思路。相关研究成果在Acta Pharmaceutica Sinica B、 J Ethnopharmacol等药学、中药药理学领域的国际权威期刊发表SCI 论文5篇，中文核心期刊2篇; 申请专利2 项，1项获授权（201610871707.9），1项已公开（CN202010141918.3）； 培养博士研究生3 名，硕士研究生1名。.