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.
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Acknowledgements
This study was supported by the National New Drug Creation Program of China (2015ZX09501007-001 to Jian-hua Sun and 2018ZX09201017-004 to Li-kun Gong) and the “Strategic Priority Research Program” of the Chinese Academy of Sciences (XDA12050305 to Li-kun Gong).
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XXY, YTZ, FGM and LKG designed the research and wrote the manuscript. XXY, HLL, SYW, XLY, and JHS conducted the experiments. HLL contributed to the pathological analysis, and YTZ performed data analysis.
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Yan, Xx., Li, Hl., Zhang, Yt. et al. A new recombinant MS-superoxide dismutase alleviates 5-fluorouracil-induced intestinal mucositis in mice. Acta Pharmacol Sin 41, 348–357 (2020). https://doi.org/10.1038/s41401-019-0295-8
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DOI: https://doi.org/10.1038/s41401-019-0295-8
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