Article

A new recombinant MS-superoxide dismutase alleviates 5-fluorouracil-induced intestinal mucositis in mice

Authors: Xiao-xia Yan1,2, Hai-long Li3,3, Yi-ting Zhang1,2, Shou-yan Wu1,2, Heng-lei Lu1, Xiao-lu Yu1,2, Fan-guo Meng3,3, Jian-hua Sun1, Li-kun Gong1,2
1 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 Institute of Molecular Enzymology, Medical College of Soochow University, Suzhou 215123, China
3 Redox Medical Center for Public Health, Soochow University, Suzhou 215123, China
Correspondence to: Jian-hua Sun: jhsun@cdser.simm.ac.cn, Li-kun Gong: lkgong@cdser.simm.ac.cn,
DOI: 10.1038/s41401-019-0295-8
Received: 31 January 2019
Accepted: 6 August 2019
Advance online: 10 September 2019

Abstract

Intestinal mucositis is a common side effect of anticancer regimens that exerts a negative impact on chemotherapy. Superoxide dismutase (SOD) is a potential therapy for mucositis but efficient product is not available because the enzyme is degraded following oral administration or induces an immune reaction after intravascular infusion. Multi-modified Stable Anti-Oxidant Enzymes® (MS-AOE®) is a new recombinant SOD with better resistance to pepsin and trypsin. We referred it as MS-SOD to distinguish from other SODs. In this study we investigated its potential to alleviate 5-FU-induced intestinal injury and the mechanisms. An intestinal mucositis model was established in C57/BL6 mice by 5-day administration of 5-FU (50 mg/kg every day, ip). MS-SOD (800 IU/10 g, ig) was given once daily for 9 days. 5-FU caused severe mucositis with intestinal morphological damage, bodyweight loss and diarrhea; MS-SOD significantly decreased the severity. 5-FU markedly increased reactive oxygen species (ROS) and inflammatory cytokines in the intestine which were ameliorated by MS-SOD. Furthermore, MS-SOD modified intestinal microbes, particularly reduced Verrucomicrobia, compared with the 5-FU group. In Caco2 cells, MS-SOD (250–1000 U/mL) dose-dependently decreased tBHP-induced ROS generation. In RAW264.7 cells, MS-SOD (500 U/mL) had no effect on LPS-induced inflammatory cytokines, but inhibited iNOS expression. These results demonstrate that MS-SOD can scavenge ROS at the initial stage of injury, thus play an indirect role in anti-inflammatory and barrier protein protection. In conclusion, MS-SOD attenuates 5-FU-induced intestinal mucositis by suppressing oxidative stress and inflammation, and influencing microbes. MS-SOD may exert beneficial effect in prevention of intestinal mucositis during chemotherapy in clinic.
Keywords: manganese superoxide dismutase; 5-fluorouracil; chemotherapy; intestinal mucositis; diarrhea; oxidative stress; cytokines; intestinal microbes

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