Dipeptidyl peptidase-4 enzyme inhibition and its impacts on hepatic preneoplasia: a new avenue for liver cancer management.

AIMS: Dipeptidyl peptidase-4 enzyme (DPP-4) was reported to be associated with immune stimulation, resistance to anti-neoplastic agents and lipid accumulation. Dysregulated DPP-4 expression was reported in various malignant tumors such as hepatocellular carcinoma. Hence, the influence of sitagliptin, an inhibitor of DPP-4 enzyme, was performed in vitro (HepG2 cells) and in vivo (mouse model of hepatic preneoplasia). MAIN METHODS: The effect of sitagliptin was investigated in vitro via MTT assay. The in vivo model of hepatic preneoplasia was conducted by weekly intraperitoneal injection of 75 mg/kg of diethylnitrosamine (DEN) for five successive weeks. Mice were treated daily with sitagliptin (50 mg/kg, p.o.) starting 1 week after DEN injection till the end of the experiment. KEY FINDINGS: Sitagliptin exerted a significant cytotoxic effect on HepG2 cells, which was dependent on elevating mRNA expression of p53 and BAX/BCL2. Sitagliptin also improved serum liver enzymes and attenuated histopathological alterations in mice. These changes were accompanied by reducing liver GGT, DPP-4, CYP2E1, GGT-P, NF-κB and PCNA along with increasing CYP3A4. Furthermore, sitagliptin attenuated DEN-induced liver DNA damage and inflammation. SIGNIFICANCE: These findings shed the light on the role of DPP-inhibitors in the future of cancer therapy and management.