【作者】 姚璎；

【导师】 李大伟；

【作者基本信息】 上海交通大学 ， 微生物与生化药学， 2010， 硕士

【摘要】 由于肿瘤类型的复杂性和多样性以及肿瘤对单一靶点药物的抗药性,目前化疗药物所针对的靶点远远不能满足肿瘤治疗的需要,因而急待开发针对新型抗肿瘤药物的靶点。我们在研究抗锥虫亮氨酰tRNA合成酶(tbLeuRS)抑制剂对人源细胞毒性的过程中,发现有些抑制剂对人源亮氨酰tRNA合成酶(hLeuRS, LARS)有明显抑制,并可以抑制人的肿瘤细胞生长。由此我们提出:人源亮氨酰tRNA合成酶作为抗肿瘤药物的新靶点是可能的,而针对人源亮氨酰tRNA合成酶的抑制剂也有可能成为新型抗肿瘤药物。本课题试图在分子、细胞和动物水平验证亮氨酰tRNA合成酶成为抗肿瘤靶点的可能性,并对抑制这一靶点的抗肿瘤分子机制作出初步推断。研究结果表明,由于结构的相似性,部分根据锥虫亮氨酰tRNA合成酶模拟设计的抑制物可以抑制人的亮氨酰tRNA合成酶(hLeuRS),并由此抑制人源细胞的增殖。亮氨酰tRNA合成酶抑制物(hLRSI)对抑制肿瘤细胞增殖有一定的选择性而这种选择性可能是由于肿瘤细胞在一定条件下比非肿瘤细胞增殖速度快造成的。与抑制蛋白合成的放线菌酮作用机制不同,hLRSI可能通过激活依赖p53的p21信号传导通道促进细胞早期凋亡,并使细胞周期阻断在G0/G1期。动物实验表明,hLRSI对移植瘤有一定的抑制作用,而对动物毒性较小。综上所述,我们初步证实了亮氨酰tRNA合成酶是一个抗肿瘤药物的潜在靶点。这为进一步研究并利用这一靶点设计、合成、筛选新型抗肿瘤药物打下了基础。更多还原

【Abstract】 Cancer is a deadly human disease that has multiple molecular causes and various types of cell origins. In addition, cancer cells often develop resistance to single-target anti-cancer drugs. Therefore, new anti-cancer targets are constantly called for in order to develop new chemotherapy drugs. We have found that some trypanosoma Leucyl-tRNA-synthetase (tbLeuRS) inhibitors also inhibited the growth of human cancer cells by the inhibition of human Leucyl-tRNA synthetase (hLeuRS/LARS). We propose that hLeuRS is a potential anti-cancer target and the inhibitors of this enzyme may develop into a new line of chemotherapy drugs. This thesis will try to verify this hypothesis through the design of a series of molecular, cellular and animal model experiments. The possible molecular mechanism of cancer cell inhibition by hLeuRS inhibitors is also touched on.This thesis shows that some compounds designed to inhibit tbLeuRS also inhibit hLeuRS in vitro, and hLeuRS inhibitors suppress tumor cell proliferation. The results also show hLeuRS inhibitor selectively inhibits cancer cells and this selectivity may reflect the preferred inhibition of fast growing cells, a common characteristic of cancer cells. Indeed, in a xenograft mouse model, hLeuRS inhibitor showed inhibition to tumor growth while had little sign of toxicity. Different from cyclohexmide, a general protein synthesis inhibitor, hLeuRS inhibitor activates p53 dependent p21 signaling pathway and promotes early apoptosis and G0/G1 cell cycle blocking.Taken together, this thesis proposed and showed hLeuRS is a potential anticancer drug target. These results will warrant the further study of hLeuRS as an anti-cancer target for the development of new lines of anti-cancer drugs.更多还原