Perindopril sensitizes hepatocellular carcinoma to chemotherapy: A possible role of leptin / Wnt/ β-catenin axis with subsequent inhibition of liver cancer stem cells

Sherin Zakaria; Shady Allam; Alaa E El-Sisi

doi:10.1016/j.jsps.2022.06.019

Perindopril sensitizes hepatocellular carcinoma to chemotherapy: A possible role of leptin / Wnt/ β-catenin axis with subsequent inhibition of liver cancer stem cells

Saudi Pharm J. 2022 Aug;30(8):1170-1180. doi: 10.1016/j.jsps.2022.06.019. Epub 2022 Jun 22.

Authors

Sherin Zakaria¹, Shady Allam², Alaa E El-Sisi³

Affiliations

¹ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kaferelsheikh University, 33516, Kaferelsheikh, Egypt.
² Department of Pharmacology and Toxicology, Faculty of Pharmacy, Menoufia University, 32511, Menoufia, Egypt.
³ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, 31512, Tanta, Egypt.

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death. The major challenge in managing HCC is the resistance to chemotherapy. Leptin hormone is associated with different oncogenic pathways implicated in drug resistance. Angiotensin II was found to decrease the production and secretion of leptin.

Objective: This study investigated the potential role of an ACEI perindopril as a chemosensitizer agent to sorafenib.

Method: HCC was induced in mice using a single dose of diethylnitrosamine DENA (200 mg/kg) followed by phenobarbital 0.05% in drinking water for 16 weeks. Mice were then treated with perindopril (1 mg/kg/day), Sorafenib (30 mg/kg/day), or both of them for another four weeks. Leptin, VEGF, MMP-9, Cyclin D1, EpCAM, and β-catenin were measured using immunoassay while Wnt and ALDH1 were assayed using western blotting assay.

Results: Perindopril whether alone or in combination with sorafenib decrease liver enzymes and preserve the liver architecture. Our study revealed that perindopril significantly increased the antineoplastic, antiangiogenic as well as anti-metastatic effects of sorafenib. This effect was correlated with the downregulation of the leptin / Wnt / β-catenin pathway and overexpression of ALDH1 while downregulation of EpCAM.

Conclusion: This study presents perindopril as a potential chemosensitizer agent that works through decreased expression of the leptin / Wnt / β-catenin pathway.

Keywords: ABC, ATP binding box; ACEI, Angiotensin converting enzyme inhibitors; ALDH1; ALDH1, Aldehyde dehydrogenases 1; ALT, Alanineaminotransferase; ANG II, Angiotensin II; APC, adenomatous polyposis coli protein; AST, Aspartate aminotransferase; DENA, Diethylnitrosamine; EpCAM, Epithelial cell adhesion molecule; GSK 3β, glycogen synthase kinase-3β; HCC, Hepatocellular carcinoma; LCSC, Liver cancer stem cells; Leptin; MMP-9, Metalloproteinase-9; PBS, Phosphate-buffered saline; PDGFR-β, platelet-derived growth factor receptor; PRIN, Perindopril; Perindopril; SOR, Sorafenib; VEGF, Vascular endothelial growth factor; Wnt; mTOR, Mammalian target of rapamycin; β-catenin.