A novel hybrid peptide targeting EGFR-expressing cancers
A novel hybrid peptide targeting EGFR-expressing cancers
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DOI：
10.1016/j.ejca.2010.10.021
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发表时间：
2011-03-01
影响因子：
8.4
通讯作者：
Kawakami, Koji
中科院分区：
文献类型：
--
作者：
Kohno, Masayuki;Horibe, Tomohisa;Kawakami, Koji
一些潜在的分子靶向抗癌药物主要集中在抑制受体酪氨酸激酶和肿瘤生长，但这些酪氨酸激酶抑制剂（TKI）已被报道在癌细胞中激酶相关信号分子基因突变导致耐药。为了克服这一问题，我们设计了一种新的靶向抗癌“杂交肽”EGFR-裂解肽，其中表皮生长因子受体（EGFR）结合肽与一种新设计的含有富含阳离子氨基酸的裂解型肽结合，该肽可分解细胞膜以杀死癌细胞。在本报告中，研究了egfr裂解肽在多种人类癌症和正常细胞系中的细胞毒活性。研究发现，这种新型裂解肽的构象改变使其能够选择性地与癌细胞膜结合，并且由于其获得的协同作用，杂交肽在暴露后10分钟内就能选择性地破坏癌细胞。egfr裂解肽对K-ras突变的tki耐药癌细胞具有足够的体外细胞毒活性。此外，体内分析显示，该肽在人类K-ras突变阴性和阳性癌症的小鼠异种移植模型中均显示出显著的抗肿瘤活性。因此，混合肽可以成为一种独特而有力的新型癌症靶向治疗工具。(C) 2010 Elsevier Ltd.版权所有。
Several potential molecular-targeted anticancer drugs focus on the inhibition of receptor tyrosine kinase and tumour growth, but these tyrosine kinase inhibitors (TKI) have been reported that the mutations of kinase-related signal molecule genes in cancer cells lead to the drug resistance. To overcome this issue, we have designed a novel targeting anticancer 'hybrid-peptide' EGFR-lytic peptide, in which epidermal growth factor receptor (EGFR) binding peptide is conjugated with a newly designed lytic-type peptide containing cationic-rich amino acids that disintegrates the cell membrane to kill cancer cells. In this report, cytotoxic activity of EGFR-lytic peptide was investigated in various human cancer and normal cell lines. It was found that the resulting conformational change in the novel lytic peptide enabled it to bind selectively to the membrane of cancer cells, and due to its acquired synergistic action, hybrid peptide demonstrated selective destruction of cancer cells as swiftly as 10 min after exposure. Treatment with EGFR-lytic peptide exerted a sufficient in vitro cytotoxic activity against TKI-resistant cancer cells with K-ras mutations. Moreover, in vivo analyses revealed that this peptide displayed significant antitumour activity in mouse xenograft models of both human K-ras mutation negative and positive cancers. Thus, hybrid peptide can be a unique and powerful tool for a new cancer-targeted therapy. (C) 2010 Elsevier Ltd. All rights reserved.