title: An EGFR/HER2-Bispecific and enediyne-energized fusion protein shows high efficacy against esophageal cancer.
abstract: 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.
authors.affiliation: Department of Microbiology, Xinxiang Medical University, Xinxiang, China.
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Guo
authors.affiliation: School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Xinxiang Medical University, Xinxiang, China; Department of Pathology, University of Illinois at Chicago, Chicago, United States of America.
authors.forename: Wan-Cai
authors.initials: WC
authors.lastname: Yang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Perking Union Medical College, Beijing, China.
authors.forename: Sheng-Hua
authors.initials: SH
authors.lastname: Zhang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Perking Union Medical College, Beijing, China.
authors.forename: Yong-Su
authors.initials: YS
authors.lastname: Zhen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D053143:Caspase 2 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000378:metabolism; D053281:Enediynes / Q000737:chemistry*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D053143:Caspase 2; D053179:Caspase 7; D003546:Cysteine Endopeptidases; D053281:Enediynes; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C490360:CASP2 protein, human; C505520:CASP7 protein, human