Abstract
BackgroundEndostatin (ES) inhibits endothelial cell proliferation, migration, invasion, and tube formation. It also shows antiangiogenesis and antitumor activities in several animal models. Endostatin specifically targets tumor vasculature to block tumor growth. Lidamycin (LDM), which consists of an active enediyne chromophore (AE) and a non-covalently bound apo-protein (LDP), is a member of chromoprotein family of antitumor antibiotics with extremely potent cytotoxicity to cancer cells. Therefore, we reasoned that endostatin-lidamycin (ES-LDM) fusion proteins upon energizing with enediyne chromophore may obtain the combined capability targeting tumor vasculature and tumor cell by respective ES and LDM moiety.MethodsIn this study, we designed and obtained two new endostatin-based fusion proteins, endostatin-LDP (ES-LDP) and LDP-endostatin (LDP-ES). In vitro, the antiangiogenic effect of fusion proteins was determined by the wound healing assay and tube formation assay and the cytotoxicity of their enediyne-energized analogs was evaluated by CCK-8 assay. Tissue microarray was used to analyze the binding affinity of LDP, ES or ES-LDP with specimens of human lung tissue and lung tumor. The in vivo efficacy of the fusion proteins was evaluated with human lung carcinoma PG-BE1 xenograft and the experimental metastasis model of 4T1-luc breast cancer.ResultsES-LDP and LDP-ES disrupted the formation of endothelial tube structures and inhibited endothelial cell migration. Evidently, ES-LDP accumulated in the tumor and suppressed tumor growth and metastasis. ES-LDP and ES show higher binding capability than LDP to lung carcinoma; in addition, ES-LDP and ES share similar binding capability. Furthermore, the enediyne-energized fusion protein ES-LDP-AE demonstrated significant efficacy against lung carcinoma xenograft in athymic mice.ConclusionsThe ES-based fusion protein therapy provides some fundamental information for further drug development. Targeting both tumor vasculature and tumor cells by endostatin-based fusion proteins and their enediyne-energized analogs probably provides a promising modality in cancer therapy.
Highlights
Endostatin (ES) inhibits endothelial cell proliferation, migration, invasion, and tube formation
Endostatin (ES), a 20-kDa fragment cleaved from the collagen XVIII COOH terminus that inhibits endothelial cell proliferation and migration, is a well-known angiogenesis inhibitor, which shows antiangiogenesis and antitumor activities in several animal models
Construction, preparation and biochemical characterization of ES-Lidamycin apo-protein (LDP), LDP-ES and their enediyneenergized analogs DNA fragments encoding LDP and ES fusion proteins were obtained by PCR and molecular cloning techniques
Summary
Endostatin (ES) inhibits endothelial cell proliferation, migration, invasion, and tube formation. It shows antiangiogenesis and antitumor activities in several animal models. Several antiangiogenic agents are currently under investigation in clinical trials. In contrast to those conventional therapies that kill tumor cells directly, angiogenesis inhibitors suppress tumor growth by blocking the formation of new blood vessels, which provide oxygen and nutrients for tumor growth. Endostatin (ES), a 20-kDa fragment cleaved from the collagen XVIII COOH terminus that inhibits endothelial cell proliferation and migration, is a well-known angiogenesis inhibitor, which shows antiangiogenesis and antitumor activities in several animal models. IGFII-mediated signaling and T-type Ca2+ channels involve the function of ES [5,6]
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