兰州大学机构库 >生命科学学院
NGR-抗菌肽的抗肿瘤活性
Alternative TitleAntitumor activity of NGR-antimicrobial peptide
张伟
Thesis Advisor栗震亚 ; 王锐
2008-05-14
Degree Grantor兰州大学
Place of Conferral兰州
Degree Name硕士
Keyword血管生成 氨肽酶N 连接子 凋亡 NGR序列 线粒体 鸡胚绒毛尿囊膜
Abstract肿瘤的存活、生长以及代谢都需要有新的血管的生长(血管生成)。所以,通过抑制血管生成来治疗肿瘤是一种新的策略。氨肽酶N(CD13)是一种跨膜肽酶,分子量为140,000,在一些实体瘤和肿瘤血管中高表达。NGR序列是氨肽酶的配体,这种序列能够通过肽和蛋白质之间的相互作用而结合到膜上,并通过受体介导的内吞途径内化进入到细胞内。 我们设计了两种NGR靶向肽,K2和K3,它们的序列如下: K1(KSL):KKVVFKVKFK K2:CNGRC-G-G- KKVVFKVKFK K3:CNGRC-G-F-L-G- KKVVFKVKFK KSL是一个通过组合化学的方法筛选出来的10肽,对细菌有很高的毒性,但是对于正常的真核细胞毒性很小。K2和K3之间的主要区别在于连接子。K2的连接子是非降解的Gly-Gly,它的作用可增加肽的柔韧性,使空间的相互影响最小化,因为空间的影响会阻碍肽的结合以及对膜的破坏能力。而K3的连接子是可降解的Gly-Phe-Leu-Gly,它有助于K3进入细胞后释放抗菌肽KSL。 NGR靶向肽能够通过受体介导的途径进入细胞,然后导致线粒体的溶胀,以及通过线粒体途径引起的凋亡。 在细胞外的线粒体溶胀实验中,NGR序列能够影响抗菌肽对线粒体膜的破坏。K2和K3对线粒体的溶胀作用都小于K1。细胞增殖实验的结果说明K1,K2和K3相对于正常的小鼠成纤维细胞,对人脐静脉内皮细胞(HUVEC)更具有选择性。由于NGR序列的存在,K2和K3相对于K1对HUVEC细胞具有更高的毒性。K3对HUVEC细胞的增殖要高于K2,这可能是因为K3在进入细胞之后能释放出抗菌肽KSL。这个结果与鸡胚绒毛尿囊膜实验的结果一致。 总之,NGR靶向肽可以通过线粒体引发细胞凋亡,而且具有很低的细胞毒性,因而作为一种新的策略来治疗肿瘤。
Other AbstractTumor cell survival, growth and metastasis require persistent new blood vessel growth (angiogenesis). Consequently, a strategy has emerged to treat tumor by inhibiting angiogenesis. Aminopeptidase N (CD13) is a transmembrane ectopeptidase of Mr 140,000, and it is highly expressed on cells of some solid tumors and new blood vessels that are required for tumor growth. NGR motif is an aminopeptidase N (CD13) ligand, and this motif can bind to membrane via peptide:protein interactions and then is internalized via receptor-mediated pathways. We have designed two NGR-peptides, K2 and K3. Their sequences are as follows: K1 (KSL): KKVVFKVKFK K2: CNGRC-G-G- KKVVFKVKFK K3: CNGRC-G-F-L-G- KKVVFKVKFK KSL is a decapeptide that generated by combinatorial chemistry, and has high toxicity to bacteria with low toxicity to normal eukaryotic cells. The difference between K2 and K3 is the spacers. The spacer of K2 is nondegradable Gly-Gly that imparts peptide flexibility and minimizes potential steric interactions that would prevent binding and/or membrane disruption. However, the spacer of K3 is degradable Gly-Phe-Leu-Gly that can contribute to release KSL after K3 enter cells. NGR-peptide can be internalized into cells via receptor-mediated pathways, and then induce mitochondrial swelling and mitochondria dependent cell apoptosis. In the assay of mitochondria swelling, NGR motif affects the disruption of antimicrobial peptides on mitochondria membrane. The K2 and K3’ abilities of mitochondria swelling are less than K1. The result of cell proliferation assay showed that K1, K2 and K3 can selectively inhibit the proliferation of the human umbilical vein endothelial cell line HUVEC, but has lower cytotoxicity to normal murine fibroblasts. K2 and K3 have more toxicity to HUVEC than K1 due to the NGR motif. Maybe K3 can release antimicrobial peptide KSL after enterring cells, so its ability of inhibitting HUVEC cells proliferation is higher than K2. The result is in accordence with that of chicken chorioallantoic membrane (CAM) assay. In summary, NGR-peptide may offer a novel therapeutic strategy in the treatment of tumor by inducing mitochondria dependent cell apoptosis, considerring its relatively lower cytoxicity to normal cells.
URL查看原文
Language中文
Document Type学位论文
Identifierhttps://ir.lzu.edu.cn/handle/262010/221919
Collection生命科学学院
Recommended Citation
GB/T 7714
张伟. NGR-抗菌肽的抗肿瘤活性[D]. 兰州. 兰州大学,2008.
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