Transcytosis, Antitumor Activity and Toxicity of Staphylococcal Enterotoxin C2 as an Oral Administration Protein Drug

Wenbin Zhao,Yingchun Xu,Liqiang Pan,Shuqing Chen,Wenhui Liu,Yangyang Li,Ding Ding

doi:10.3390/toxins8060185

Wenbin Zhao, Yingchun Xu + Show 5 more

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https://doi.org/10.3390/toxins8060185

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Abstract

Staphylococcal enterotoxin C2 (SEC2) is a classical superantigen (SAg), which can tremendously activate T lymphocytes at very low dosage, thus exerting its powerful antitumor activity. As an intravenous protein drug and a bacterial toxin, SEC2 has some limitations including poor patient compliance and toxic side effects. In this research, we devoted our attention to studying the antitumor activity and toxicity of SEC2 as a potential oral administration protein drug. We proved that His-tagged SEC2 (SEC2-His) could undergo facilitated transcytosis on human colon adenocarcinoma (Caco-2) cells and SEC2-His was detected in the blood of rats after oral administration. Furthermore, oral SEC2-His caused massive cytokine release and immune cell enrichment around tumor tissue, leading to inhibition of tumor growth in vivo. Meanwhile, although SEC2-His was dosed up to 32 mg/kg in mice, no significant toxicity was observed. These data showed that SEC2 can cross the intestinal epithelium in an immunologically integral form, maintaining antitumor activity but with reduced systemic toxicity. Therefore, these results may have implications for developing SEC2 as an oral administration protein drug.

Highlights

Staphylococcal enterotoxins (SEs), secreted by Staphylococcus aureus, are classical models of superantigens (SAgs) [1]
Compared with Horseradish peroxidase (HRP), the rate and the total quantity of transcytosis Staphylococcal enterotoxin C2 (SEC2)-His were both significantly higher. These results showed that the transcytosis of SEC2-His from basolateral to apical surfaces by Caco-2 cells could be saturated in 18 h
SEC2 can combine in integrated molecular structure with major histocompatibility complex class II (MHC II) molecules on antigen presenting cells (APCs) to form the complex

Summary

Introduction

Staphylococcal enterotoxins (SEs), secreted by Staphylococcus aureus, are classical models of superantigens (SAgs) [1]. SEs can directly bind to the antigenic groove of major histocompatibility complex class II (MHC II) molecules and the beta-chain variable region (Vβ) of the T-cell receptor in the complete form, stimulate numerous T-cells for proliferation and to release massive amounts of cytokines like interleukin (IL)-2, IL-4, tumor necrosis factor (TNF) and interferon-γ (IFN-γ) [2,3,4]. SEs could show powerful antitumor effects in vitro and in vivo. SEs include SEA, SEB, SEC, SED, SEE, SEG, SEH, SEI and SEU [1,6]. In China, staphylococci injection is widely used in cancer therapy, and the main effective component is claimed to be SEC2 [8]

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