具有a-glucosidase抑制活性的新型穿心莲内酯衍生物抗细胞黏附和血管生成作用及机制研究

项目名称： 具有a-glucosidase抑制活性的新型穿心莲内酯衍生物抗细胞黏附和血管生成作用及机制研究

项目编号： No.30873100

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 戴桂馥

作者单位： 郑州大学

项目金额： 25万元

中文摘要： 炎症与肿瘤发生发展密切相关。前期研究发现以穿心莲内酯(AD)为母体获得的新结构化合物AD-1对α#33889;萄糖苷酶抑制作用,抗炎、抗肿瘤转移作用均较AD大幅提高。本研究围绕肿瘤转移与炎症过程关键环节-细胞黏附、迁移和血管生成,研究阐明AD-1的作用机制。结果表明,AD-1(20 μl/L)可使鸡胚尿囊膜血管分支点数量减少75%(P<0.01)；显著抑制H22和S180荷瘤小鼠肿瘤生长,降低肿瘤血管指数(VI),使H22荷瘤小鼠VI值由4.82±2.43 mg/g降为3.14±1.69 mg/g(1.35 mmol/kg,ig;P<0.05),显著低于AD（5.10±2.13 mg/g；P<0.05）；AD-1显著上调H22荷瘤小鼠TIMP-1，下调VEGF表达,抑制血管内皮细胞迁移; 显著抑制S180荷瘤小鼠IL-1β12289;PGE2生成及iNOS活力，下调NF-kBp65表达，抑制NF-κ#26680;位移。证明抑制Slex表达,干扰白细胞/肿瘤细胞与血管内皮细胞间黏附，发挥抗炎、抗肿瘤转移作用是AD-1区别于AD的主要机制。综上，AD-1有望开发为调节肿瘤微环境，抑制肿瘤发生发展的抗肿瘤药物。

中文关键词： 穿心莲内酯衍生物；肿瘤转移；抗炎；抗血管新生；NF-κ#20449;号通路

英文摘要： It is well known that inflammation is closely related with tumorigenesis and tumor progression. In our previous studies, it was found that AD-1, a novel derivative of andrographolide(AD)which is a principle of traditional Chinese anti-inflammatory medicine, significantly increased the inhibition against αlucosidase，and increased the anti-inflammatory activity and decreased the number of pulmonary metastasis nodules in C57BL/6 mice injected with B16F-10 melanoma cells (iv) compared with AD. In this study, we mainly clarified the corresponding mechanism of AD-1 by adopting a serious of in vivo and in vitro models combined with some research methods of enzymology and cytobiology, which was focus on the key common links:cell adhesion, migration and angiogenesis both in tumor metastasis and inflammation. Results showed that the vascular branch number in the CAM was significantly reduced about 75% by AD-1(20 μl/l; P&lt;0.05); the growth of hepatoma H22 and sarcoma S180 in mice were significantly decreased and the tumor angiogenesis was remarkably inhibited by AD-1; AD-1 significantly decreased the vascular index of tumor tissue in H22 mice from 4.82 ± 2.43 to 3.14 ± 1.69 mg/g (1.35 mmol/kg,ig;P &lt; 0.05) which was lower than AD (5.10 ± 2.13; P&lt;0.05). AD-1 significantly inhibited the VEGF and increased the TIMP-1 production in serum of Hepatoma H22 mice; and also the migration of vascular endothelial cells was inhibited by AD-1. AD-1 significantly inhibited the NF-κp65 proteins expression and NF-κp65 nuclear traslocation by down-regulating the expression of IL-1βand decreased the PGE2 production and iNOS avtivity in serum of S180 tumor-bearing mice, then inhibited the proliferation and angiogenesis of the malignant tumor tissues. It was further explored that AD-1 significantly inhibited the expressions of Slex, the ligand of E-selectin, which was also observed in SGC-7901 cells，which is the key difference in mechanism of anti-inflammation and anti-metastasis between AD-1 and AD . Therefore, AD-1 is potentially to be developed as the new anti-tumor drugs, which can regulate the tumor microenvironment and inhibit the tumor development with great efficiency and low toxicity.

英文关键词： andrographolide derivatives；neoplasm metastasis；anti-inflammation； anti-angiogenesis； NF-κpathway