A ligand-based and enediyne-energized bispecific fusion protein targeting epidermal growth factor receptor and insulin-like growth factor-1 receptor shows potent antitumor efficacy against esophageal cancer

  • Authors:
    • Hai-Ying Cao
    • Xiao-Fang Guo
    • Xiao-Fei Zhu
    • Sai-Sai Li
    • Yong-Su Zhen
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  • Published online on: April 27, 2017     https://doi.org/10.3892/or.2017.5606
  • Pages: 3329-3340
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Abstract

Recent studies have revealed that the epidermal growth factor receptor (EGFR) and insulin-like growth factor-1 receptor (IGF-1R) are overexpressed in various types of human tumors and are attractive targets for anticancer drugs. In the present study, the expression of EGFR and IGF-1R in esophageal squamous cell carcinoma (ESCC) and adjacent normal tissues in a tissue microarray was firstly detected by immunohistochemical staining. In addition, their co-overexpression was observed in 48 out of 75 (64%) patients. Based on the findings, the antitumor activity of an EGFR/IGF-1R bispecific and enediyne-energized fusion protein EGF-LDP-IGF-AE, which we constructed recently by fusing two ligands (EGF and IGF-1) with an enediyne antibiotic lidamycin (LDM), on ESCC were evaluated. Binding assay indicated that the EGF-LDP-IGF protein bound to esophageal cancer cells, and then internalized into the cytoplasm. In vitro, the enediyne‑energized fusion protein EGF-LDP-IGF-AE exhibited extremely potent cytotoxicity to ESCC cells with IC50 values between 10-10 and 10-15 mol/l. In vivo, EGF-LDP‑IGF-AE also markedly suppressed the growth of human KYSE450 xenografts by 75.1% when administered at 0.3 mg/kg in a nude mouse model, and its efficacy was significantly higher than that of LDM (at maximum tolerated dosage) and mono-specific counterparts. In addition, EGF-LDP-IGF-AE arrested cell cycle progression and it concentration-dependently induced cell apoptosis as well as inhibited the activation of EGFR/IGF-1R and two major downstream signaling pathways (PI3K/AKT and RAS/MAPK). These data imply the potential clinical application of EGF-LDP-IGF-AE for ESCC patients with EGFR and/or IGF-1R overexpression.
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June-2017
Volume 37 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Cao H, Guo X, Zhu X, Li S and Zhen Y: A ligand-based and enediyne-energized bispecific fusion protein targeting epidermal growth factor receptor and insulin-like growth factor-1 receptor shows potent antitumor efficacy against esophageal cancer. Oncol Rep 37: 3329-3340, 2017
APA
Cao, H., Guo, X., Zhu, X., Li, S., & Zhen, Y. (2017). A ligand-based and enediyne-energized bispecific fusion protein targeting epidermal growth factor receptor and insulin-like growth factor-1 receptor shows potent antitumor efficacy against esophageal cancer. Oncology Reports, 37, 3329-3340. https://doi.org/10.3892/or.2017.5606
MLA
Cao, H., Guo, X., Zhu, X., Li, S., Zhen, Y."A ligand-based and enediyne-energized bispecific fusion protein targeting epidermal growth factor receptor and insulin-like growth factor-1 receptor shows potent antitumor efficacy against esophageal cancer". Oncology Reports 37.6 (2017): 3329-3340.
Chicago
Cao, H., Guo, X., Zhu, X., Li, S., Zhen, Y."A ligand-based and enediyne-energized bispecific fusion protein targeting epidermal growth factor receptor and insulin-like growth factor-1 receptor shows potent antitumor efficacy against esophageal cancer". Oncology Reports 37, no. 6 (2017): 3329-3340. https://doi.org/10.3892/or.2017.5606