Antitumor efficacy of the scFv-based fusion protein and its enediyne-energized analogue directed against epidermal growth factor receptor

Sheng, Weijin; Shang, Yue; Qin, Miao; Li, Yi; Zhen, Yong‐Su

doi:10.1097/cad.0b013e32834f9801

Cited by 9 publications

(12 citation statements)

References 25 publications

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“…However, the bioactivity of LDP and LDPbased fusion proteins also has gradually garnered our interest in recent years. LDP-based fusion protein can reportedly inhibit the growth of tumours [12]. In the current study, similar results for Fv-LDP were also obtained based on the colony formation assay and the in vivo experiments using mice bearing human hepatoma BEL-7402 and murine transplantable H22 cells ( fig.…”

Section: Discussionsupporting

confidence: 85%

“…C). The internalization rate of Fv‐LDP was lower than that of other antibody‐based fusion proteins bound to the cell membrane, which suggested that most of the Fv‐LDP might act on the surface of tumour cells but did not directly enter the tumour cells .…”

Section: Discussionmentioning

confidence: 95%

“…The binding reactivity of LDP posi-tively correlates with the expression of VEGF and EGFR in lung carcinoma tissues and the expression of VEGF and HER2 in breast carcinoma tissues [21,25]. Furthermore, integrating LDP into a ligand oligopeptide or scFv that targets EGFR has resulted in augmented binding capability to cancer cells [12,14]. These results lay the basis for the preparation of scFv-based fusion protein Fv-LDP directed against gelatinases.…”

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confidence: 99%

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A Gelatinases‐targeting scFv‐based Fusion Protein Shows Enhanced Antitumour Activity with Endostar against Hepatoma

Gao

Shang

et al. 2015

Basic Clin Pharma Tox

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Gelatinases play important roles in tumour invasion and metastasis and are thus considered promising targets for cancer therapy. In this study, a new single-chain variable fragment (scFv)-based fusion protein Fv-LDP, composed of the anti-gelatinases scFv and lidamycin apoprotein (LDP), was prepared, and its combination with angiogenesis inhibitor Endostar was then investigated. The fusion protein Fv-LDP specifically bound to various tumour cells, and its binding capability to human pulmonary giant cell carcinoma (PG) cells was higher than that of LDP. Fv-LDP inhibited the expression and secretion of gelatinases and could be internalized into tumour cells via endocytosis. Fv-LDP also suppressed the growth of human hepatoma cells and murine hepatoma 22 transplanted in Kunming mice in various degrees. In addition, Endostar could enhance the synergistic or additive inhibition of Fv-LDP on the growth, migration or invasion of human hepatoma cells shown by a colony formation assay and a transwell-based migration or invasion assay, respectively. In vivo, Fv-LDP/Endostar combination showed a significantly synergistic effect on the growth of a human hepatoma xenograft, with an inhibition rate of 80.8% compared with the Fv-LDP (44.1%) or Endostar (8.9%)-treated group. The above-mentioned results indicate that the fusion protein Fv-LDP is effective against transplantable hepatoma in mice and human hepatoma xenografts in athymic mice. Moreover, Endostar can potentiate the inhibition effect of Fv-LDP on the growth of human hepatoma cells and xenografts. These data will provide a new combined strategy for improving the therapeutic efficacy of treatments for hepatoma or other gelatinase-overexpressing tumours.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

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A Gelatinases‐targeting scFv‐based Fusion Protein Shows Enhanced Antitumour Activity with Endostar against Hepatoma

Gao

Shang

et al. 2015

Basic Clin Pharma Tox

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“…In addition, LDP displayed moderate cytotoxicity to human hepatoma Bel-7402 cells with an IC50 value of 7.05 × 10 -5 mol/l and it exerted tumor suppression on hepatoma H22 in Kunming mice [20]. The functional receptor of ES nucleolin was found to be specifically expressed on the surface of angiogenic blood vessels in tumor tissues, which endows ES low toxicity and tumor-specific distribution [7].…”

Section: Discussionmentioning

confidence: 99%

“…The activity of rebuilt molecule remains as potent as that of natural LDM. LDP, which is composed of 110 amino acid residues, showed specific binding capability to various human tumor tissues and displayed moderate cytotoxicity to Bel-7402 cells [20,21]. This specific binding capability and cytotoxicity of LDP implied its potential use as a targeting drug carrier in the design of new anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

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

Jiang

Shang

et al. 2013

BMC Cancer

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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.

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Construction of an Ec‐LDP‐D5 fusion protein that targets human epidermal growth factor receptor and its anti‐pancreatic cancer activity

Liu

Song

Zuo

et al. 2017

Precision Radiation Oncology

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Objective: It is well known that -defensins are mainly packaged in neutrophil granules (HNP1, HNP2, and HNP3) or secreted by intestinal Paneth cells (human defensin [HD]5 and HD6). HNP1-3 peptides are also secreted, and their accumulation in biological fluids was proposed as a tumor biomarker. It has been reported that -defensins promote tumor cell growth, but also provoke cell death at higher concentrations. The aim of the present study was to construct a novel fusion protein consisting of oligopeptides specific for human epidermal growth factor receptor (EGFR), lidamycin apoprotein (LDP), and HD5, and investigate its anti-pancreatic cancer activities.Methods: HD5 was fused to the Ec-LDP protein to obtain the Ec-LDP-D5 fusion protein by DNA recombination. Then, immunofluorescence and enzyme-linked immunosorbent assays were used to investigate the binding activities of Ec-LDP-D5 to EGFR-overexpressed cancer cells. CCK-8 assay was used to measure Ec-LDP-D5 in vitro cytotoxicity, and AnnexinV-FITC/PI staining assay was used to analyze its apoptosis-inducing efficacy. Results:The Ec-LDP-D5 fusion protein was constructed correctly and expressed in Escherichia coli in insoluble inclusion bodies. The production of Ec-LDP-D5 was 1 mg/L fermentation broth, and the purity of the fusion protein was 85% as analyzed by high-performance liquid chromatography.Ec-LDP-D5 showed strong binding activities for pancreatic cancer cells that highly express EGFR, including PNAC-1 and Aspc-1 cells. The Ec-LDP-D5 fusion protein showed more potent cytotoxicity to cancer cells compared with Ec-LDP. The results from the AnnexinV-FITC/PI staining assay also revealed that Ec-LDP-D5 significantly induced cell apoptosis. Conclusion:The novel Ec-LDP-D5 fusion protein binds to EGFR specifically, and shows potent cytotoxicity and apoptosis-inducing activities towards pancreatic cancer cells, which suggests that it would be a promising cancer therapeutics candidate.

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Antitumor efficacy of the scFv-based fusion protein and its enediyne-energized analogue directed against epidermal growth factor receptor

Cited by 9 publications

References 25 publications

A Gelatinases‐targeting scFv‐based Fusion Protein Shows Enhanced Antitumour Activity with Endostar against Hepatoma

A Gelatinases‐targeting scFv‐based Fusion Protein Shows Enhanced Antitumour Activity with Endostar against Hepatoma

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

Construction of an Ec‐LDP‐D5 fusion protein that targets human epidermal growth factor receptor and its anti‐pancreatic cancer activity

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