Genetically engineered endostatin-lidamycin fusion proteins effectively inhibit tumor growth and metastasis

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.

A novel antibody–drug conjugate anti-CD19(Fab)-LDM in the treatment of B-cell non-Hodgkin lymphoma xenografts with enhanced anticancer activity

“…Though, LDM is a potent ''warhead'' drug, it lacks the targeting function resulting in systemic toxicity. Previous studies have shown that LDM-related enediyneenergized fusion proteins presented stronger inhibitory activity in tumor targeting therapy [36][37][38]. In this study, we conjugated the anti-CD19(Fab) antibody with LDM by genetic engineering to generate ADC anti-CD19(Fab)-LDM, which has a stable structure and delivers drug to the target cells.…”

Preliminary detection of the anti-tumour activity of indoline-2,3-dione derivative DH-12a targeting aminopeptidase N

“…H22 cells (7.5x10 6 ) in 200 µl sterile PBS were injected into 4-6-week-old female Kunming mice by tail vein injection. After 24 h, the mice were randomly divided into four groups (17). For the drug treatment, the drugs, dissolved in sterile PBS with 5% DMSO, were administered by intraperitoneal injection for 5 days and withdrawn for 2 days.…”

Correlation of Serum Levels of Endostatin with Tumor Stage in Gastric Cancer: A Systematic Review and Meta-Analysis

“…Previous studies describe multiple roles for endostatin in modulating endothelial cell behavior; for example, endothelin induces endothelial cell apoptosis and acts as a regulator of tube formation and migration and growth of endothelial cells. Thus, endothelin interfered with tumor proliferation by inhibiting the activity of tumor-stimulating growth factors [ 12 , 13 ]. In addition, a few studies have shown that endostatin inhibits tumor angiogenesis and tumor metastasis by limiting blood supply to tumors, thereby depriving tumors of nutrients, and was considered as a potential anticancer maker in treatment for malignant tumors [ 14 – 16 ].…”