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

• Published in: Acta pharmacologica Sinica 2020-03, Vol.41 (3), p.348-357
• Main Authors: Yan, Xiao-xia, Li, Hai-long, Zhang, Yi-ting, Wu, Shou-yan, Lu, Heng-lei, Yu, Xiao-lu, Meng, Fan-guo, Sun, Jian-hua, Gong, Li-kun
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Administration, Oral; Animals; Biomedical and Life Sciences; Biomedicine; Chemotherapy; Cytokines; Diarrhea; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Fluorouracil - metabolism; Immunoglobulins; Immunology; Inflammation; Injections, Intraperitoneal; Internal Medicine; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intestine; Lipopolysaccharides; Male; Medical Microbiology; Mice; Mice, Inbred C57BL; Mucositis; Nitric-oxide synthase; Oral administration; Oxidants; Oxidation; Oxidative stress; Pepsin; Pharmacology/Toxicology; Reactive oxygen species; Recombinant Proteins - administration & dosage; Recombinant Proteins - metabolism; Superoxide dismutase; Superoxide Dismutase - administration & dosage; Superoxide Dismutase - metabolism; Trypsin; Vaccine
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-019-0295-8

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.