Perindopril Sensitizes Hepatocellular Carcinoma to Chemotherapy: A Possible Role of Leptin / Wnt/ β-catenin Axis with Subsequent Inhibition of Liver Cancer Stem Cells

Overview

Journal Saudi Pharm J

Specialty Pharmacy

Date 2022 Sep 27

PMID 36164573

Authors

Sherin Zakaria

Shady Allam

Alaa E El-Sisi

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Perindopril Ameliorates Sodium Valproate-Induced Rat Model of Autism: Involvement of Sirtuin-1, JAK2/STAT3 Axis, PI3K/Akt/GSK-3β Pathway, and PPAR-Gamma Signaling.

Alnakhli A, Saleh A, Kabel A, Estfanous R, Borg H, Alsufyani K Medicina (Kaunas). 2024; 60(11).

PMID: 39596986 PMC: 11596946. DOI: 10.3390/medicina60111802.

Clinical Significance of Plasma Leptin and Its Receptors mRNA Expression in Craniopharyngiomas: A Prospective Study.

Xiao Y, Wu W, Cai K, Jin L, Jia Y, Qiao N Biomolecules. 2023; 13(7).

PMID: 37509115 PMC: 10377231. DOI: 10.3390/biom13071078.

In Vitro Drug Repurposing: Focus on Vasodilators.

Ribeiro E, Costa B, Vasques-Novoa F, Vale N Cells. 2023; 12(4).

PMID: 36831338 PMC: 9954697. DOI: 10.3390/cells12040671.

References

Beretta G, Cassinelli G, Pennati M, Zuco V, Gatti L . Overcoming ABC transporter-mediated multidrug resistance: The dual role of tyrosine kinase inhibitors as multitargeting agents. Eur J Med Chem. 2017; 142:271-289. DOI: 10.1016/j.ejmech.2017.07.062. View

Carr B . Hepatocellular carcinoma: current management and future trends. Gastroenterology. 2004; 127(5 Suppl 1):S218-24. DOI: 10.1053/j.gastro.2004.09.036. View

Terris B, Cavard C, Perret C . EpCAM, a new marker for cancer stem cells in hepatocellular carcinoma. J Hepatol. 2009; 52(2):280-1. DOI: 10.1016/j.jhep.2009.10.026. View

Zhu Y, Zheng B, Wang H, Chen L . New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol Sin. 2017; 38(5):614-622. PMC: 5457690. DOI: 10.1038/aps.2017.5. View

Wilhelm S, Carter C, Tang L, Wilkie D, McNabola A, Rong H . BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004; 64(19):7099-109. DOI: 10.1158/0008-5472.CAN-04-1443. View

Tang W, Chen Z, Zhang W, Cheng Y, Zhang B, Wu F . The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther. 2020; 5(1):87. PMC: 7292831. DOI: 10.1038/s41392-020-0187-x. View

Ma S, Chan K, Lee T, Tang K, Wo J, Zheng B . Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol Cancer Res. 2008; 6(7):1146-53. DOI: 10.1158/1541-7786.MCR-08-0035. View

Nasr M, Selima E, Hamed O, Kazem A . Targeting different angiogenic pathways with combination of curcumin, leflunomide and perindopril inhibits diethylnitrosamine-induced hepatocellular carcinoma in mice. Eur J Pharmacol. 2013; 723:267-75. DOI: 10.1016/j.ejphar.2013.11.022. View

Pandit H, Li Y, Li X, Zhang W, Li S, Martin R . Enrichment of cancer stem cells via β-catenin contributing to the tumorigenesis of hepatocellular carcinoma. BMC Cancer. 2018; 18(1):783. PMC: 6091111. DOI: 10.1186/s12885-018-4683-0. View

10.

Dostalek M, Hardy K, Milne G, Morrow J, Chen C, Gonzalez F . Development of oxidative stress by cytochrome P450 induction in rodents is selective for barbiturates and related to loss of pyridine nucleotide-dependent protective systems. J Biol Chem. 2008; 283(25):17147-57. PMC: 2427356. DOI: 10.1074/jbc.M802447200. View

11.

Dong N, Shi X, Wang S, Gao Y, Kuang Z, Xie Q . M2 macrophages mediate sorafenib resistance by secreting HGF in a feed-forward manner in hepatocellular carcinoma. Br J Cancer. 2019; 121(1):22-33. PMC: 6738111. DOI: 10.1038/s41416-019-0482-x. View

12.

Noguchi R, Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Yanase K . Combination of interferon-beta and the angiotensin-converting enzyme inhibitor, perindopril, attenuates murine hepatocellular carcinoma development and angiogenesis. Clin Cancer Res. 2003; 9(16 Pt 1):6038-45. View

13.

Forner A, Llovet J, Bruix J . Hepatocellular carcinoma. Lancet. 2012; 379(9822):1245-55. DOI: 10.1016/S0140-6736(11)61347-0. View

14.

Lipsey C, Harbuzariu A, Daley-Brown D, Gonzalez-Perez R . Oncogenic role of leptin and Notch interleukin-1 leptin crosstalk outcome in cancer. World J Methodol. 2016; 6(1):43-55. PMC: 4804251. DOI: 10.5662/wjm.v6.i1.43. View

15.

Kuczynski E, Lee C, Man S, Chen E, Kerbel R . Effects of Sorafenib Dose on Acquired Reversible Resistance and Toxicity in Hepatocellular Carcinoma. Cancer Res. 2015; 75(12):2510-9. PMC: 6485661. DOI: 10.1158/0008-5472.CAN-14-3687. View

16.

Zhang Y, Wang S, Li L . EF Hand Protein IBA2 Promotes Cell Proliferation in Breast Cancers via Transcriptional Control of Cyclin D1. Cancer Res. 2016; 76(15):4535-45. DOI: 10.1158/0008-5472.CAN-15-2927. View

17.

Bender M, Sifuentes C, Denver R . Leptin Induces Mitosis and Activates the Canonical Wnt/β-Catenin Signaling Pathway in Neurogenic Regions of Tadpole Brain. Front Endocrinol (Lausanne). 2017; 8:99. PMC: 5421298. DOI: 10.3389/fendo.2017.00099. View

18.

Yu F, Fu R, Liu L, Wang X, Wu T, Shen W . Leptin-Induced Angiogenesis of EA.Hy926 Endothelial Cells the Akt and Wnt Signaling Pathways and . Front Pharmacol. 2019; 10:1275. PMC: 6836761. DOI: 10.3389/fphar.2019.01275. View

19.

Yan D, Avtanski D, Saxena N, Sharma D . Leptin-induced epithelial-mesenchymal transition in breast cancer cells requires β-catenin activation via Akt/GSK3- and MTA1/Wnt1 protein-dependent pathways. J Biol Chem. 2012; 287(11):8598-612. PMC: 3318705. DOI: 10.1074/jbc.M111.322800. View

20.

Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang H . EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009; 136(3):1012-24. PMC: 2828822. DOI: 10.1053/j.gastro.2008.12.004. View