Long-term treatment with Sitagliptin, a dipeptidyl peptidase-4 inhibitor, reduces colon carcinogenesis and reactive oxygen species in 1,2-dimethylhydrazine-induced rats

Type 2 diabetes mellitus (T2DM) and insulin resistance (IR) increase colon cancer risk. Antidiabetic drugs stabilizing incretin hormones, such as inhibitors of dipeptidyl peptidase-4 activity (DPP4i), may affect colon carcinogenesis; however, the data remain controversial. Therefore, the authors studied whether long-term administration of the DPP4i Sitagliptin (SITA) affects 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis. Male F344 rats fed a high-fat (HF) diet promoting colon carcinogenesis and IR, were induced with DMH (100 mg/kg 3 2 times). One week later, the animals were allocated to two groups: one continuing with HF diet (controls; n 5 8) and one receiving SITA (n 5 8) mixed in the diet (260 ppm). Body weight, food consumption and glycemia were not affected by SITA. Fifteen weeks after DMH, the number of the precancerous lesions mucin-depleted foci (MDF) was significantly lower in rats treated with SITA [MDF/colon: 9.5 6 0.9 and 6.4 6 0.9 in controls (n 5 8) and SITA groups (n 5 8), respectively; means 6 SE, p < 0.05]. Reactive oxygen species in the blood were also significantly lower in the SITA group [6.75 6 0.69 and 5.63 6 0.75 (H2O2 in mM) in controls (n 5 5) and SITA (n 5 6), respectively; means 6 SE, p < 0.05]. Rats treated with SITA had a lower DPP4 activity in the intestine but not in the plasma. Intestine growth morphometric parameters and colon proliferation, as proliferating cell nuclear antigen expression, were not affected by SITA. In conclusion, the results suggest a protective effect of DPP4i against colon carcinogenesis that could be exploited in chemoprevention trials