Dipeptidyl-peptidase-4 (DPP-4) inhibitor ameliorates 5-flurouracil induced intestinal mucositis
Jung Min Lee1,2, In Kyung Yoo1, Jae Min Lee1
1Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea.
Background:
Chemotherapy-induced alimentary mucositis (AM) is difficult to prevent and treatment is rarely effective. Recent study have been showed that glucagon-like peptide (GLP)-1 and GLP-2 has protective in chemotherapy-induced AM. While the DPP-4 enzyme degrades this GLP-1, the DPP-4 inhibitor blocks the degradation process and raises the concentration of GLP-1. This study aimed to assess the role of DPP-4 inhibitor, a well-known hypoglycemic agent, on chemotherapy-induced AM.
Methods:
Twenty-four 6-week-old male C57BL/6 mice were divided into 4 groups: control, 5-fluorouracil (5-FU), DPP-4 inhibitor, and saline (DPP-4i), and DPP-4 inhibitor and 5-FU (DPP-4i + 5-FU). Mucositis was induced by intraperitoneal injection of 5-FU (400 mg/kg). DPP-4 inhibitor (50 mg/kg) was administered orally for four days starting the day before 5-FU administration. Post 72 h of 5-FU injection, mice were sacrificed and body weight change, diarrhea score, villus height, villus/crypt ratio, histologic characteristics including goblet cell count, and mRNA expression of inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6, were assessed.
Results:
Daily body weight change was not statistically significant between the 5-FU and the DPP-4i + 5-FU group (P = 0.571). Diarrhea score was significantly different between these two groups (P = 0.033). In the 5-FU group, the villus height was not maintained well, the epithelial lining was irregular, and inflammatory cell infiltration was observed. Goblet cell count in the DPP-4i + 5-FU group was significantly higher than in the 5-FU group (P = 0.007). However, in the DPP-4i + 5-FU group, the villus height, epithelial lining, and crypt structure were better maintained than in the 5-FU group. Compared with the control group, mRNA expression of TNF-α was significantly up-regulated in the 5-FU group. Moreover, mRNA expression of TNF-α in the DPP-4i + 5-FU group was down-regulated compared to the 5-FU group. However, IL-6 in the 5-FU group was significantly down-regulated compared to the control, there was no significant difference in expression of IL-6 between the 5-FU and DPP4i + 5-FU group.
Conclusion:
DPP-4 inhibitor can improve 5-FU induced AM and, therefore, has potential as an alternative treatment for chemotherapy-induced AM.
Insights
DPP-4 inhibitors show promise in treating chemotherapy-induced alimentary mucositis (AM). This study found that DPP-4 inhibitors improved gut health and reduced inflammation in mice receiving 5-FU chemotherapy.
Area of Science:
- Gastroenterology
- Pharmacology
- Oncology
Background:
- Chemotherapy-induced alimentary mucositis (AM) presents significant challenges in cancer care due to limited prevention and treatment options.
- Glucagon-like peptide (GLP)-1 and GLP-2 have demonstrated protective effects against chemotherapy-induced AM.
- Dipeptidyl peptidase-4 (DPP-4) inhibitors block the degradation of GLP-1, thereby increasing its concentration and potentially mitigating AM.
Purpose of the Study:
- To investigate the therapeutic potential of DPP-4 inhibitors in managing chemotherapy-induced AM.
- To evaluate the efficacy of a DPP-4 inhibitor in a mouse model of 5-fluorouracil (5-FU) induced mucositis.
Main Methods:
- Twenty-four male C57BL/6 mice were allocated into four groups: control, 5-FU, DPP-4 inhibitor alone, and DPP-4 inhibitor plus 5-FU.
- Alimentary mucositis was induced using intraperitoneal injection of 5-FU. The DPP-4 inhibitor was administered orally starting the day before 5-FU.
- Evaluated parameters included body weight change, diarrhea score, intestinal villus height, villus/crypt ratio, goblet cell count, and mRNA expression of TNF-α and IL-6.
Main Results:
- The DPP-4 inhibitor plus 5-FU group exhibited a significantly lower diarrhea score compared to the 5-FU alone group.
- Histological analysis revealed improved villus height, epithelial lining, and crypt structure in the DPP-4 inhibitor plus 5-FU group versus the 5-FU group.
- DPP-4 inhibitor administration led to a significant downregulation of TNF-α mRNA expression compared to the 5-FU group, suggesting reduced inflammation.
Conclusions:
- DPP-4 inhibitors demonstrate a significant capacity to ameliorate 5-FU-induced alimentary mucositis in a preclinical model.
- These findings suggest that DPP-4 inhibitors hold potential as an effective therapeutic strategy for managing chemotherapy-induced AM.
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