Sitagliptin enhances the effects of 5-fluorouracil in cancer colon through inhibition of thymidylate synthase

Abstract

5-fluorouracil (5-FU) is a regularly used treatment for colon cancer because of its low cost. It functions by interfering with DNA replication in cancer cells. However, its effectiveness is often limited by the development of chemoresistance. This study evaluates the cytotoxic effects of combined 5-fluorouracil (5-FU) and Sitagliptin (Sita), a medication primarily used for diabetes but also possessing potential cancer-modulating properties on Caco-2 cells and explores the molecular interactions between sitagliptin and thymidylate synthase (TS) through in vitro and in silico analyses. Treatments for Caco-2 cells included different doses of 5-FU, sitagliptin, and their combinations. Using MTT assays, the cytotoxic effects were evaluated. The binding affinities of sitagliptin, 5-FU, and raltitrexed (a recognized TS inhibitor) to the TS protein were examined using molecular docking experiments. Results of the MTT assay indicated a dose-dependent reduction in Caco-2 cell viability for both 5-FU and sitagliptin, with the combination treatment showing a substantially greater reduction in cell viability. The molecular docking study revealed that sitagliptin binds strongly to the TS active site. In summary, the combined administration of 5-FU and sitagliptin enhances cytotoxicity against Caco-2 cells, suggesting that sitagliptin may potentiate the efficacy of 5-FU in colon cancer treatment. The strong binding affinity of sitagliptin to TS supports its potential role in improving chemosensitivity. To confirm the therapeutic effects of this combination in patients with colon cancer, our findings call for more molecular and clinical research.