Defensins play an essential role in innate immunity. In this study, a novel recombinant β-defensin that targets the epidermal growth factor receptor (EGFR) was designed and prepared. The EGFR-targeting β-defensin consists of an EGF-derived oligopeptide (Ec), a β-defensin-1 peptide (hBD1) and a lidamycin-derived apoprotein (LDP), which serves as the "scaffold" for the fusion protein (Ec-LDP-hBD1). Ec-LDP-hBD1 effectively bound to EGFR highly expressed human epidermoid carcinoma A431 cells. The cytotoxicity of Ec-LDP-hBD1 to EGFR highly expressed A431 cells was more potent than that to EGFR low-expressed human lung carcinoma A549 and H460 cells (the IC₅₀ values in A431, A549, and H460 cells were 1.8 ± 0.55, 11.9 ± 0.51, and 5.19 ± 1.21 μmol/L, respectively); in addition, the cytotoxicity of Ec-LDP-hBD1 was much stronger than that of Ec-LDP and hBD1. Moreover, Ec-LDP-hBD1 suppressed cancer cell proliferation and induced mitochondria-mediated apoptosis. Its in vivo anticancer action was evaluated in athymic mice with A431 and H460 xenografts. The mice were administered Ec-LDP-hBD1 (5, 10 mg/kg, i.v.) two times with a weekly interval. Administration of Ec-LDP-hBD1 markedly inhibited the tumor growth without significant body weight changes. The in vivo imaging further revealed that Ec-LDP-hBD1 had a tumor-specific distribution with a clear image of localization. The results demonstrate that the novel recombinant EGFR-targeting β-defensin Ec-LDP-hBD1 displays both selectivity and enhanced cytotoxicity against relevant cancer cells by inducing mitochondria-mediated apoptosis and exhibits high therapeutic efficacy against the EGFR-expressed carcinoma xenograft. This novel format of β-defensin, which induces mitochondrial-mediated apoptosis, may play an active role in EGFR-targeting cancer therapy.

中文翻译：

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靶向EGFR的，β-防御素特异的融合蛋白通过线粒体介导的细胞凋亡对EGFR表达的人类癌症表现出很高的治疗功效。

防御素在先天免疫中起重要作用。在这项研究中，设计并制备了靶向表皮生长因子受体（EGFR）的新型重组β-防御素。靶向EGFR的β-防御素由EGF衍生的寡肽（Ec），β-defensin-1肽（hBD1）和利多霉素衍生的载脂蛋白（LDP）组成，充当融合蛋白的“支架”（ Ec-LDP-hBD1）。Ec-LDP-hBD1有效结合到EGFR高表达的人表皮样癌A431细胞。Ec-LDP-hBD1对EGFR高表达的A431细胞的毒性比对EGFR低表达的人肺癌A549和H460细胞的毒性更强（IC ₅₀A431，A549和H460电池中的值分别为1.8±0.55、11.9±0.51和5.19±1.21μmol/ L）; 另外，Ec-LDP-hBD1的细胞毒性比Ec-LDP和hBD1强得多。此外，Ec-LDP-hBD1抑制癌细胞增殖并诱导线粒体介导的细胞凋亡。在具有A431和H460异种移植的无胸腺小鼠中评估了其体内抗癌作用。每周两次给小鼠施用Ec-LDP-hBD1（5，10 mg / kg，iv）两次。施用Ec-LDP-hBD1可以显着抑制肿瘤的生长，而体重没有显着变化。体内成像进一步显示，Ec-LDP-hBD1具有肿瘤特异性分布，并具有清晰的定位图像。结果表明，新型重组靶向EGFR的β-防御素Ec-LDP-hBD1通过诱导线粒体介导的细胞凋亡对相关癌细胞显示选择性和增强的细胞毒性，并且对EGFR表达的癌异种移植物显示出高治疗功效。β-防御素的这种新形式可诱导线粒体介导的细胞凋亡，在靶向EGFR的癌症治疗中可能发挥积极作用。