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.
Highlights
Esophageal cancer is one of the most common cancers, as well as the sixth most common cause of cancer-related deaths in the world
Preparation of energized fusion proteins According to our previous approach, the genes coding for fusion proteins Ec-LDP-Hr, Ec-LDP, and LDP-Hr were constructed and the encoded proteins were expressed in the periplasmic space of E.coli
To characterize the molecular mechanisms involved in the cytotoxicity and apoptosis-induction of Ec-LDP-Hr-active enediyne chromophore (AE), we examined its effects on the expression of apoptosis related molecules and several key molecules in the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) signaling pathways
Summary
Esophageal cancer is one of the most common cancers, as well as the sixth most common cause of cancer-related deaths in the world. The northern regions in Henan province of China have the highest incidence of esophageal cancer, the esophageal squamous cell carcinoma (ESCC) [1,2]. Due to the disadvantages of chemotherapy agents, such as severe toxic side-effects, the high incidence of drug-resistance, and little effects on survival, there is an urgent need for the development of novel effective therapeutic agents, targeting specific molecular abnormalities in esophageal carcinomas, especially those in the human epidermal growth factor receptor (HER) family [6]. EGFR overexpression occurs in 30%– 90% [9,10], and HER2 overexpression ranges from 19%–43% [11] Overexpression of both EGFR and HER2 was observed in 18%–25% patients with esophageal cancer [12,13]. An agent targeting both EGFR and HER2 would exhibit more effective therapeutic effects on esophageal cancer patients
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