title: Long-term treatment with Sitagliptin, a dipeptidyl peptidase-4 inhibitor, reduces colon carcinogenesis and reactive oxygen species in 1,2-dimethylhydrazine-induced rats.
abstract: 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 × 2 times). One week later, the animals were allocated to two groups: one continuing with HF diet (controls; n = 8) and one receiving SITA (n = 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 ± 0.9 and 6.4 ± 0.9 in controls (n = 8) and SITA groups (n = 8), respectively; means ± SE, p < 0.05]. Reactive oxygen species in the blood were also significantly lower in the SITA group [6.75 ± 0.69 and 5.63 ± 0.75 (H2 O2 in mM) in controls (n = 5) and SITA (n = 6), respectively; means ± 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.
authors: Section of Pharmacology and Toxicology, NEUROFARBA Department, University of Florence, Florence, Italy.
authors: Angelo Pietro
authors: AP
authors: Femia
authors: Laura
authors: L
authors: Raimondi
authors: Giulia
authors: G
authors: Maglieri
authors: Maura
authors: M
authors: Lodovici
authors: Edoardo
authors: E
authors: Mannucci
authors: Giovanna
authors: G
authors: Caderni
mesh_terms: D019813:1,2-Dimethylhydrazine; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000097:blood / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008297:Male; D009077:Mucins / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000097:blood; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D009077:Mucins; D011719:Pyrazines; D017382:Reactive Oxygen Species; D014230:Triazoles; D018819:Dipeptidyl Peptidase 4; D019813:1,2-Dimethylhydrazine; D000068900:Sitagliptin Phosphate
keywords: Sitagliptin; colon carcinogenesis; incretin-based therapies; insulin resistance; mucin-depleted foci; preneoplastic lesions