Selective cancer cell cytotoxicity of enantiomeric 9-mer peptides derived from beetle defensins depends on negatively charged phosphatidylserine on the cell surface
Selective cancer cell cytotoxicity of enantiomeric 9-mer peptides derived from beetle defensins depends on negatively charged phosphatidylserine on the cell surface
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DOI：
10.1016/j.peptides.2008.12.019
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发表时间：
2009-04-01
期刊：
影响因子：
3
通讯作者：
Yamakawa, Minoru
中科院分区：
文献类型：
--
作者：
Iwasaki, Takashi;Ishibashi, Jun;Yamakawa, Minoru
以两种甲虫的43-mer昆虫防御素为基础，设计合成了4个对映体9-mer肽，分别命名为D-肽A、B、C和D。D-9-mer肽保持了与原始肽类似的细菌膜破坏活性，并且还显示出对不同癌细胞系的不同程度的生长抑制活性。在这些肽中，D-肽B对小鼠骨髓瘤细胞系P3-X63-Ag 8.653表现出最高的选择性癌细胞毒性。流式细胞术和扫描电子显微镜分析显示D-肽B破坏小鼠骨髓瘤膜的构建，而对正常白细胞没有细胞毒性作用。此外，在各种癌细胞系中观察到癌细胞膜表面带负电荷的磷脂酰丝氨酸（PS）密度与对D-9-mer肽的敏感性之间的强相关性。这些结果表明，D-9-mer肽具有负电荷依赖性的选择性癌细胞毒性，靶向癌细胞膜中的PS。此外，在D-肽B和地塞米松的组合中观察到对小鼠骨髓瘤的协同生长抑制活性。这些结果表明，D-9-mer肽是有前途的候选人，为新的抗癌药物。皇冠版权所有（c）2008由爱思唯尔公司出版。All rights reserved.
Four enantiomeric 9-mer peptides named D-peptide A, B, C and D were designed and synthesized on the basis of 43-mer insect defensins from two beetles. The D-9-mer peptides maintained bacterial membrane disruptive activity similar to the original peptides and also showed various extents of growth inhibitory activity against different cancer cell lines. Of these peptides, D-peptide B exhibited the highest selective cancer cell cytotoxicity against the mouse myeloma cell line, P3-X63-Ag8.653. Flow cytometric and scanning electron microscopic analysis revealed D-peptide B disrupts mouse myeloma membrane construction, whereas no cytotoxic effect on normal leukocytes was observed. Moreover, a strong correlation between negatively charged phosphatidylserine (PS) density in cancer cell membrane surface and sensitivity to D-9-mer peptides were observed in various cancer cell lines. These results suggest that D-9-mer peptides have negative charge-dependent selective cancer cell cytotoxicity targeting PS in the cancer cell membrane. In addition, synergic growth inhibitory activity against mouse myeloma was observed in combinations of D-peptide B and dexamethasone. These results suggest D-9-mer peptides are promising candidates for novel anticancer drugs. Crown Copyright (c) 2008 Published by Elsevier Inc. All rights reserved.