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Antitumor Activity of NGR-antimicrobial Peptide

Author: ZhangWei
Tutor: LiZhenYa；WangRui
School: Lanzhou University
Course: Biochemistry and Molecular Biology
Keywords: angiogenesis Aminopeptidase N NGR motif spacer mitochondria apoptosis CAM
CLC: R730.5
Type: Master's thesis
Year: 2008
Downloads: 197
Quote: 0
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Abstract

Tumor 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):KKVVFKVKFKK2:CNGRC-G-G-KKVVFKVKFKK3:CNGRC-G-F-L-G-KKVVFKVKFKKSL 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.

Antitumor Activity of NGR-antimicrobial Peptide

Abstract

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