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

  • Environ Toxicol Pharmacol. 2021 Aug:86:103668. doi: 10.1016/j.etap.2021.103668.
Ahmed G Abd Elhameed  1 ,  Manar G Helal  2 ,  Eman Said  3 ,  Hatem A Salem  2
Affiliations
  • 1. Dep. of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; Dep. of Pharmacology, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt.
  • 2. Dep. of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
  • 3. Dep. of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. Electronic address: [email protected].
PMID: 33945853 DOI: 10.1016/j.etap.2021.103668
Abstract

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.

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