Oncotarget

Research Papers:

A bispecific enediyne-energized fusion protein targeting both epidermal growth factor receptor and insulin-like growth factor 1 receptor showing enhanced antitumor efficacy against non-small cell lung cancer

Xiao-fang Guo _, Xiao-fei Zhu, Hai-ying Cao, Gen-shen Zhong, Liang Li, Bao-guo Deng, Ping Chen, Pei-zhen Wang, Qing-fang Miao and Yong-su Zhen

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:27286-27299. https://doi.org/10.18632/oncotarget.15933

Metrics: HTML 1378 views  |   ?  


Abstract

Xiao-Fang Guo1, Xiao-Fei Zhu2,3, Hai-Ying Cao1, Gen-Shen Zhong4, Liang Li5, Bao-Guo Deng1, Ping Chen1, Pei-Zhen Wang1, Qing-Fang Miao5, Yong-Su Zhen5

1Department of Microbiology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China

2Department of Clinical Immunology, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China

3Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang, China

4Laboratory of Cancer Biotherapy, Institute of Neurology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China

5Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Perking Union Medical College, Beijing, China

Correspondence to:

Xiao-Fang Guo, email: guoxiaofang_1981@126.com

Yong-Su Zhen, email: zhenysm@126.com

Keywords: EGFR, IGF-1R, lidamycin, bispecific fusion protein, NSCLC

Received: July 04, 2016     Accepted: February 20, 2017     Published: March 06, 2017

ABSTRACT

Epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-1R) both overexpressed on non-small cell lung cancer (NSCLC) and are known cooperatively to promote tumor progression and drug resistance. This study was to construct a novel bispecific fusion protein EGF-IGF-LDP-AE consisting of EGFR and IGF-IR specific ligands (EGF and IGF-1) and lidamycin, an enediyne antibiotic with potent antitumor activity, and investigate its antitumor efficacy against NSCLC. Binding and internalization assays showed that EGF-IGF-LDP protein could bind to NSCLC cells with high affinity and then internalized into cells with higher efficiency than that of monospecific proteins. In vitro, the enediyne-energized analogue of bispecific fusion protein (EGF-IGF-LDP-AE) displayed extremely potent cytotoxicity to NSCLC cell lines with IC50<10-11 mol/L. Moreover, the bispecific protein EGF-IGF-LDP-AE was more cytotoxic than monospecific proteins (EGF-LDP-AE and LDP-IGF-AE) and lidamycin. In vivo, EGF-IGF-LDP-AE markedly inhibited the growth of A549 xenografts, and the efficacy was more potent than that of lidamycin and monospecific counterparts. EGF-IGF-LDP-AE caused significant cell cycle arrest and it also induced cell apoptosis in a dosage-dependent manner. Pretreatment with EGF-IGF-LDP-AE inhibited EGF-, IGF-stimulated EGFR and IGF-1R phosphorylation, and blocked two main downstream signaling molecules AKT and ERK activation. These data suggested that EGF-LDP-IGF-AE protein would be a promising targeted agent for NSCLC patients with EGFR and/or IGF-1R overexpression.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 15933