Efficacy of ginsenoside treatment to alleviate anticancer-drug induced mucoenteritis in mice
DOI:
https://doi.org/10.33910/2687-1270-2022-3-3-336-347Keywords:
5-fluorouracil, anticancer drug, Ginsenoside, mucositis, enteritis, NF-κBAbstract
5-fluorouracil (5-FU), which is widely used as an anticancer drug, causes enteritis due to disruption of mucosal tissue, resulting in diarrhoea and body weight loss. Ginsenoside Rd (GRd) and ginsenoside Re (GRe) are two of the saponins contained in carrots. Their anti-inflammatory effects on the digestive system have been reported, but their effects on small intestinal mucositis have not been studied much. This study investigated the effect of GRd and GRe on 5-FU-induced mucoenteritis. GRd and GRe did not affect weight loss or exacerbation of diarrhoea due to 5-FU administration in mice. Histopathological observations showed that 5-FU reduced the shortening of intestinal villi and the number of crypts and cells compared to the vehicle group. However, co-administration of GRd and GRe, significantly suppressed the decrease in the number of small intestinal crypts and cells in the crypt by 5-FU treatment. It indicates that 5-FU-induced enteritis is attenuated by the co-administration of GRd and GRe. The expression of NF-κB was increased by 5-FU administration and this increase was clearly suppressed in the group that was co-administered GRd. Although the anti-inflammatory effects of GRd and GRe have been reported based on various mechanisms in many models, the mechanism of their enteritis-suppressing action in anticancer drug-induced enteritis has not been clarified. It was reported that the anti-inflammatory effect of GRd was due to the suppression of NF-κB expression; we concluded that NF-κB may be one of the molecules involved in the suppression of 5-FU-incuced enteritis.
References
Benson, A. B., Ajani, J. A., Catalano, R. B. et al. (2004) Recommended guidelines for the treatment of cancer treatment-induced diarrhea. Journal of Clinical Oncology, vol. 22, no. 14, pp. 2918–2926. https://doi.org/10.1200/JCO.2004.04.132 (In English)
Chang, C.-T., Ho, T.-Y., Lin, H. et al. (2012) 5-fluorouracil induced intestinal mucositis via nuclear factor-κB activation by transcriptomic analysis and in vivo bioluminescence imaging. PLoS ONE, vol. 7, no. 3, article e31808. https://doi.org/10.1371/journal.pone.0031808 (In English)
Derrien, M., van Baarlen, P., Hooiveld, G. et al. (2011) Modulation of mucosal immune response, tolerance, and proliferation in mice colonized by the mucin-degrader Akkermansia muciniphila. Frontiers in Microbiology, vol. 2, article 166. https://doi.org/10.3389/fmicb.2011.00166 (In English)
Dranitsaris, G., Maroun, J., Shah, A. (2005) Severe chemotherapy-induced diarrhea in patients with colorectal cancer: A cost of illness analysis. Supportive Care in Cancer, vol. 13, no. 5, pp. 318–324. https://doi.org/10.1007/s00520-004-0738-7 (In English)
Duncan, M., Grant, G. (2003) Oral and intestinal mucositis—causes and possible treatments. Alimentary Pharmacology and Therapeutics, vol. 18, no. 9, pp. 853–874. https://doi.org/10.1046/j.1365-2036.2003.01784.x (In English)
Engevik, A. C., Kaji, I., Engevik, M. A. et al. (2018) Loss of MYO5B leads to reductions in Na+ absorption with maintenance of CFTR-dependent Cl− secretion in enterocytes. Gastroenterology, vol. 155, no. 6, pp. 1883–1897. https://doi.org/10.1053/j.gastro.2018.08.025 (In English)
Frank, D. N., Amand, A. L. St., Feldman, R. A. et al. (2007) Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 34, pp. 13780–13785. https://doi.org/10.1073/pnas.0706625104 (In English)
Hamouda, N., Sano, T., Oikawa, Y. et al. (2017) Apoptosis, dysbiosis and expression of inflammatory cytokines are sequential events in the development of 5-fluorouracil-induced intestinal mucositis in mice. Basic and Clinical Pharmacology and Toxicology, vol. 121, no. 3, pp. 159–168. https://doi.org/10.1111/bcpt.12793 (In English)
Inomata, A., Horii, I., Suzuki, K. (2002) 5-Fluorouracil-induced intestinal toxicity: What determines the severity of damage to murine intestinal crypt epithelia? Toxicology Letters, vol. 133, no. 2-3, pp. 231–240. https://doi.org/10.1016/s0378-4274(02)00204-7 (In English)
Jin, B., Zhang, C., Geng, Y., Liu, M. (2020) Therapeutic effect of Ginsenoside Rd on experimental autoimmune encephalomyelitis model mice: Regulation of inflammation and Treg/Th17 cell balance. Mediators of Inflammation, vol. 2020, article 8827527. https://doi.org/10.1155/2020/8827527 (In English)
Khan, I., Ullah, N., Zha, L. et al. (2019) Alteration of gut microbiota in inflammatory bowel disease (IBD): Cause or consequence? IBD treatment targeting the gut microbiome. Pathogens, vol. 8, no. 3, article 126. https://doi.org/10.3390/pathogens8030126 (In English)
Lee, I.-A., Hyam, S. R., Jang, S. E. et al. (2012) Ginsenoside Re ameliorates inflammation by inhibiting the binding of lipopolysaccharide to TLR4 on macrophages. Journal of Agricultural and Food Chemistry, vol. 60, no. 38, pp. 9595–9602. https://doi.org/10.1021/jf301372g (In English)
Liu, C., Wang, J., Yang, Y. et al. (2018) Ginsenoside Rd ameliorates colitis by inducing p62-driven mitophagy-mediated NLRP3 inflammasome inactivation in mice. Biochemical Pharmacology, vol. 155, pp. 366–379. https://doi.org/10.1016/j.bcp.2018.07.010 (In English)
Lv, H., Li, Y., Xue, C. et al. (2022) Aquaporin: Targets for dietary nutrients to regulate intestinal health. Journal of Animal Physiology and Animal Nutrition, vol. 106, no. 1, pp. 167–180. https://doi.org/10.1111/jpn.13539 (In English)
Mori, K., Kondo, T., Kamiyama, Y. et al. (2003) Preventive effect of Kampo medicine (Hangeshashin-to) against irinotecan-induced diarrhea in advanced non-small-cell lung cancer. Cancer Chemotherapy and Pharmacology, vol. 51, no. 5, pp. 403–406. https://doi.org/10.1007/s00280-003-0585-0 (In English)
Ozawa, N., Onda, T., Hayashi, K. et al. (2020) Effects of topical Hangeshashinto (TJ-14) on chemotherapy-induced oral mucositis. Cancer Management and Research, vol. 12, pp. 1069–1078. https://doi.org/10.2147/CMAR.S238306 (In English)
Ribeiro, S. B., de Araujo, A. A., de Araujo Junior, R. F. et al. (2017) Protective effect of dexamethasone on 5-FU-induced oral mucositis in hamsters. PLoS ONE, vol. 12, no. 10, article e0186511. https://doi.org/10.1371/journal.pone.0186511 (In English)
Sakai, H., Sagara, A., Matsumoto, K. et al. (2013) 5-Fluorouracil induces diarrhea with changes in the expression of inflammatory cytokines and aquaporins in mouse intestines. PLoS ONE, vol. 8, no. 1, article e54788. https://doi.org/10.1371/journal.pone.0054788 (In English)
Shih, Y.-C. T., Xu, Y., Elting, L. S. (2007) Costs of uncontrolled chemotherapy-induced nausea and vomiting among working-age cancer patients receiving highly or moderately emetogenic chemotherapy. Cancer, vol. 110, no. 3, pp. 678–685. https://doi.org/10.1002/cncr.22823 (In English)
Vodenkova, S., Buchler, T., Cervena, K. et al. (2020) 5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future. Pharmacology and Therapeutics, vol. 206, article 107447. https://doi.org/10.1016/j.pharmthera.2019.107447 (In English)
Wang, L., Zhang, Y., Wang, Z. et al. (2012) Inhibitory effect of ginsenoside-Rd on carrageenan-induced inflammation in rats. Canadian Journal of Physiology and Pharmacology, vol. 90, no. 2, pp. 229–236. https://doi.org/10.1139/y11-127 (In English)
Xi, S., Zhai, X., Wang, Y. et al. (2021) The Ciji-Hua’ai-Baosheng II formula attenuates chemotherapy-induced anorexia in mice with H22 hepatocellular carcinoma. Frontiers in Pharmacology, vol. 12, article 715824. https://doi.org/10.3389/fphar.2021.715824 (In English)
Yang, X. L., Guo, T. K., Wang, Y. H. et al. (2012) Ginsenoside Rd attenuates the inflammatory response via modulating p38 and JNK signaling pathways in rats with TNBS-induced relapsing colitis. International Immunopharmacology, vol. 12, no. 2, pp. 408–414. https://doi.org/10.1016/j.intimp.2011.12.014 (In English)
Yin, W., Zhong, G., Fan, H., Xia, H. (2019) The effect of compound Sophora on fluorouracil and oxaliplatin resistance in colorectal cancer cells. Evidence-Based Complementary and Alternative Medicine, vol. 2019, article 7564232. https://doi.org/10.1155/2019/7564232 (In English)
Yousefi-Manesh, H., Dejban, P., Mumtaz, F. et al. (2020) Risperidone attenuates acetic acid-induced colitis in rats through inhibition of TLR4/NF-kB signaling pathway. Immunopharmacology and Immunotoxicology, vol. 42, no. 5, pp. 464–472. https://doi.org/10.1080/08923973.2020.1808987 (In English)
Zhang, X., Wang, Y., Ma, C. et al. (2016) Ginsenoside Rd and ginsenoside Re offer neuroprotection in a novel model of Parkinson’s disease. American Journal of Neurodegenerative Diseases, vol. 5, no. 1, pp. 52–61. https://pubmed.ncbi.nlm.nih.gov/27073742 (In English)
Zhong, C., Jiang, C., Ni, S. et al. (2020) Identification of bioactive anti-angiogenic components targeting tumor endothelial cells in Shenmai injection using multidimensional pharmacokinetics. Acta Pharmaceutica Sinica B, vol. 10, no. 9, pp. 1694–1708. https://doi.org/10.1016/j.apsb.2019.12.011 (In English)
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