新型吡唑啉酮希夫碱钌配合物抗骨肉瘤机制研究

项目名称： 新型吡唑啉酮希夫碱钌配合物抗骨肉瘤机制研究

项目编号： No.81502334

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 赵成亮

作者单位： 承德医学院

项目金额： 18万元

中文摘要： 骨肉瘤是起源于骨骼的高度恶性肿瘤。化疗是主要治疗手段，但由于肿瘤耐药性问题，严重影响了化疗效果，同时大剂量化疗副反应大。研制出新型高效、低毒、高选择性的抗骨肉瘤化疗药尤为紧迫。钌类化合物被认为是最有希望成为替代铂类化疗药的物质，其不仅具有优异、广谱的抗癌活性，而且毒性低。基于此我们前期合成了四（1-对甲苯基-3-甲基-4-呋喃甲酰基吡唑啉酮缩对甲苯胺）合钌（III)这一新型钌配合物，为世界首创，前期研究发现其能良好的抑制骨肉瘤细胞增值，同时显示其能诱导骨肉瘤细胞凋亡。据此通过该钌配合物与骨肉瘤DNA相互作用测定，细胞内活性氧变化及线粒体膜电位（△ψm）测定，Western-blot检测死亡受体家族蛋白、Bcl-2 家族蛋白，明确配合物是否紊乱线粒体功能平衡，以及能否抑制 AKT 信号通路诱导肿瘤细胞凋亡。研究将明确该钌配合物对骨肉瘤的作用机理，为研发出新型高效、低毒化疗药物提供基础。

中文关键词： 骨肉瘤；化疗；钌配合物；希夫碱；吡唑啉酮

英文摘要： Osteosarcoma is a highly malignant tumor originated in the bone, which is mainly treated through chemotherapy. However, the chemotherapy effect is seriously affected because of the tumor resistance, and the high-dose of chemotherapy medicines brings huge side effects. Therefore, it’s of particularly urgency to develop a new highly efficient, low toxic and highly selective medicine against osteosarcoma. Ruthenium compounds are considered to be the most promising alternative to platinum-based chemotherapy medicines with its excellent and broad-spectrum anti-cancer activity and low toxicity.Based on the above, we pre-synthesized the new ruthenium complexes tetra{4-[(Z)-( p-tolylamino) (2-furyl)methylene]-3-methyl-1-phenylpyrazol-5-onato} ruthenium(III) , which is first in the world. Early studies have found that it can inhibit osteosarcoma cell proliferation well and induce apoptosis in osteosarcoma. Whether the balance of mitochondrial function can be disordered and the apoptosis in osteosarcoma can be inhibited induced by AKT signal is tested through the measurement of ruthenium complexes and DNA interaction, changes in intracellular reactive oxygen, mitochondrial membrane potential, the dead receptor family proteins and Bcl-2 family proteins with Western-blot. The study will define the mechanism of this new ruthenium complex, and will lay the foundation for the research and development of a new highly efficient and low toxic chemotherapy medicine against osteosarcoma.

英文关键词： Osteosarcoma;Chemotherapy;Ruthenium compound;schiff base;pyrazolone