Saxagliptin defers thioacetamide-induced hepatocarcinogenesis in rats: A novel suppressive impact on Wnt/Hedgehog/Notch1 signaling

Aim: Hepatocellular carcinoma (HCC) is a highly invasive form of hepatic Cancer. It is a highly intricate disease with multiple pathophysiological mechanisms underlying its pathogenesis.

Materials and methods: The results of the current investigation shed light on the ability of saxagliptin (SAXA) (12.5 mg/kg) to defer HCC progression in an experimental model of thioacetamide (TAA)-induced hepatocarcinogenesis.

Results: SAXA administration improved liver function biomarkers, with a concomitant histopathological recovery. Mechanistically, the observed hepatoprotective impact was associated with significant suppression of the hepatic content of Wnt3a, β-catenin, Notch1, Smo, and Gli2 and enhanced expression of GSK 3β. Nevertheless, the hepatic expression of PCNA, P53, and cyclin D1 was significantly enhanced, with a parallel increase in the tumor expression of Caspase-3. Thus, it appears that SAXA significantly enhanced tumor Apoptosis, with concomitant suppression of HCC proliferation.

Conclusion: SAXA deferred experimentally-induced HCC via suppressing Wnt/Hedgehog/Notch1 Signaling, with enhanced tumor Apoptosis and suppressed proliferation.

HCC; Hedgehog; Notch1; Saxagliptin; Wnt; β-catenin.