The Challenges of Recombinant Endostatin in Clinical Application: Focus on the Different Expression Systems and Molecular Bioengineering

Abstract

Angiogenesis plays an essential role in rapid growing and metastasis of the tumors. Inhibition of angiogenesis is a putative strategy for cancer therapy. Endostatin (Es) is an attractive anti-angiogenesis protein with some clinical application challenges including; short half-life, instability in serum and requirement to high dosage. Therefore, production of recombinant endostatin (rEs) is necessary in large scale. The production of rEs is difficult because of its structural properties and is high-cost. Therefore, this review focused on the different expression systems that involved in rEs production including; mammalian, baculovirus, yeast, and Escherichia coli (E. coli) expression systems. The evaluating of the results of different expression systems declared that none of the mentioned systems can be considered to be generally superior to the other. Meanwhile with considering the advantages and disadvantage of E. coli expression system compared with other systems beside the molecular properties of Es, E. coli expression system can be a preferred expression system for expressing of the Es in large scale. Also, the molecular bioengineering and sustained release formulations that lead to improving of its stability and bioactivity will be discussed. Point mutation (P125A) of Es, addition of RGD moiety or an additional zinc biding site to N-terminal of Es , fusing of Es to anti-HER2 IgG or heavy-chain of IgG, and finally loading of the endostar by PLGA and PEG- PLGA nanoparticles and gold nano-shell particles are the effective bioengineering methods to overcome to clinical changes of endostatin.

Exploring three different expression systems for recombinant expression of globins: Escherichia coli, Pichia pastoris and Spodoptera frugiperda

“…These three expression systems are widely used and in previous studies they have been compared for their recombinant expression of e.g. G-protein-coupled receptors [17], endostatin [18] and rabbit liver carboxylesterases [19]. We investigate their advantages and disadvantages for the expression of globins in general.…”

The role of VEGF in the diagnosis and treatment of malignant pleural effusion in patients with non‑small cell lung cancer (Review)

“…Endostar also has a longer half-life than endostatin, with much improved medicinal properties and efficacy, resulting in a significant improvement of its biological function ( 45 ). It is now a common angiogenesis antagonist used to treat lung cancer; in particular, it is used for the management of relapse and metastasis in patients with NSCLC ( 46 ), and has been widely used in clinical practice to treat other tumors, including squamous cell carcinoma ( 47 ).…”

“…Given the wide variety of antitumor growth effects of endostatin, the following mechanistic themes have been speculated for the antiangiogenic effects of endostatin/endostar. Firstly, endostatin/endostar has been demonstrated to act on the endothelial cells of newly formed blood vessels, inhibit endothelial cell migration and induce endothelial cell apoptosis, thus resulting in limited tumor growth ( 47 ). Secondly, endostatin/endostar can downregulate the expression of Neuropilin-1 and VEGFA, which are two potent proangiogenic growth factors in numerous types of tumor due to their actions in triggering endothelial cell proliferation ( 48 ).…”

“…In most stage II–IV clinical studies, endostar was administered at 30–60 mg/m 2 , intravenously for 3–4 h/day for 1–14 days. Increasing evidence indicates that the antitumor effects of endostar are time- and dose-dependent; prolongation of administration time and a gradual increase in its blood level can improve its antitumor effects ( 47 ). When it was administered intraperitoneally (i.p.)…”

“…The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma and adenocarcinoma, but there are several other types that occur less frequently. All types can occur in unusual histological variants and as mixed cell-type combinations and thus vary in metastatic features and VEGF-VEGFR functional signatures ( 47 ). Therefore, various types of NSCLC may differ in their response to VEGF-targeted strategies for the management of associated MPE.…”