An EGFR/HER2-Bispecific and enediyne-energized fusion protein shows high efficacy against esophageal cancer.
An EGFR/HER2-Bispecific and enediyne-energized fusion protein shows high efficacy against esophageal cancer.
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DOI：
10.1371/journal.pone.0092986
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Zhen YS
中科院分区：
文献类型：
--
作者：
Guo XF;Zhu XF;Yang WC;Zhang SH;Zhen YS
食管癌是最常见的癌症之一，由于缺乏有效的治疗药物，其5年生存率不足10%。Ec-LDP-Hr-AE是一种新开发的双特异性enediyine激活融合蛋白，靶向表皮生长因子受体（EGFR）和表皮生长因子受体2 (HER2)，研究其对食管癌的抗肿瘤活性。融合蛋白Ec-LDP-Hr-AE由两种寡肽配体和一种用于受体结合和细胞杀伤的烯二因抗生素利达霉素（LDM）组成。目前的研究表明，Ec-LDP-Hr与食管鳞状细胞癌（ESCC）细胞具有高亲和力结合，并且enediyine激活的融合蛋白Ec-LDP-Hr- ae对EGFR和HER2表达差异的ESCC细胞表现出强大的细胞毒性。Ec-LDP-Hr-AE能引起EC9706和KYSE150细胞明显的G2-M阻滞，并能诱导ESCC细胞凋亡，且呈剂量依赖性。Western blot检测显示，Ec-LDP-Hr-AE能促进caspase-3和caspase-7活性以及PARP的裂解。此外，Ec-LDP-Hr-AE通过降低EGFR和HER2的磷酸化来抑制细胞增殖，并进一步抑制其下游信号分子的激活。在体内，在耐受剂量下，Ec-LDP-Hr-AE对携带人ESCC细胞KYSE150异种移植物的裸鼠的肿瘤生长抑制率为88%。上述结果表明，Ec-LDP-Hr-AE对ESCC具有较强的抗肿瘤作用，有望成为食管癌靶向治疗的候选药物。
Esophageal cancer is one of the most common cancers, and the 5-year survival rate is less than 10% due to lack of effective therapeutic agents. This study was to evaluate antitumor activity of Ec-LDP-Hr-AE, a recently developed bispecific enediyne-energized fusion protein targeting both epidermal growth factor receptor (EGFR) and epidermal growth factor receptor 2 (HER2), on esophageal cancer. The fusion protein Ec-LDP-Hr-AE consists of two oligopeptide ligands and an enediyne antibiotic lidamycin (LDM) for receptor binding and cell killing, respectively. The current study demonstrated that Ec-LDP-Hr had high affinity to bind to esophageal squamous cell carcinoma (ESCC) cells, and enediyne-energized fusion protein Ec-LDP-Hr-AE showed potent cytotoxicity to ESCC cells with differential expression of EGFR and HER2. Ec-LDP-Hr-AE could cause significant G2-M arrest in EC9706 and KYSE150 cells, and it also induced apoptosis in ESCC cells in a dosage-dependent manner. Western blot assays showed that Ec-LDP-Hr-AE promoted caspase-3 and caspase-7 activities as well as PARP cleavage. Moreover, Ec-LDP-Hr-AE inhibited cell proliferation via decreasing phosphorylation of EGFR and HER2, and further exerted inhibition of the activation of their downstream signaling molecules. In vivo, at a tolerated dose, Ec-LDP-Hr-AE inhibited tumor growth by 88% when it was administered to nude mice bearing human ESCC cell KYSE150 xenografts. These results indicated that Ec-LDP-Hr-AE exhibited potent anti-caner efficacy on ESCC, suggesting it could be a promising candidate for targeted therapy of esophageal cancer.
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