AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Abd El-Fattah E.E.; Saber S.; Youssef M.E.; Eissa H.; El-Ahwany E.; Amin N.A.; Alqarni M.; Batiha G.E.-S.; Obaidullah A.J.; Kaddah M.M.Y.; Ahmed Gaafar A.G.; Mourad A.A.E.; Mostafa-Hedeab G.; Abdelhamid A.M.

Journal: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

Publication Date: 12 January 2022

Volume / Issue: Volume 12

Article No.: 720173

ISSN: 16639812

DOI: 10.3389/fphar.2021.720173

Scopus: View on Scopus

Document Type: Article

Access: All Open Access; Gold Open Access; Green Open Access

Authors and Affiliations

Abd El-Fattah E.E., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Saber S., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Youssef M.E., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Eissa H., Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; El-Ahwany E., Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt; Amin N.A., Department of Hematology, Theodor Bilharz Research Institute, Giza, Egypt; Alqarni M., Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif, Saudi Arabia; Batiha G.E.-S., Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt; Obaidullah A.J., Drug Exploration and Development Chair (DEDC), Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Kaddah M.M.Y., Pharmaceutical and Fermentation Industries Development Center, City of Scientific Research and Technological Applications, New Borg El-Arab, Egypt; Ahmed Gaafar A.G., Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port Said University, Port Said, Egypt; Mourad A.A.E., Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port Said University, Port Said, Egypt; Mostafa-Hedeab G., Pharmacology Department and Health Research Unit, Medical College, Jouf University, Jouf, Saudi Arabia, Pharmacology Department, Faculty of Medicine, Beni-Suef University, Beni Suef, Egypt; Abdelhamid A.M., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt

Abstract

HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC. Copyright © 2022 Abd El-Fattah, Saber, Youssef, Eissa, El-Ahwany, Amin, Alqarni, Batiha, Obaidullah, Kaddah, Ahmed Gaafar, Mourad, Mostafa-Hedeab and Abdelhamid.

Keywords

Akt; AMPKα; angiogenesis; hepatocellular carcinoma; HIF-1α; MAPK; mTOR; sitagliptin; gelatinase A; hydroxymethylglutaryl coenzyme A reductase kinase; hypoxia inducible factor 1alpha; I kappa B kinase beta; Ki 67 antigen; mammalian target of rapamycin; messenger RNA; mitogen activated protein kinase 1; mitogen activated protein kinase 14; mitogen activated protein kinase 3; monocyte chemotactic protein 1; protein Bax; protein bcl 2; protein kinase B; protein p53; transcription factor FKHRL1; transforming growth factor beta; vasculotropin; adult; animal experiment; animal model; animal tissue; antiproliferative activity; apoptosis; Article; cancer survival; controlled study; down regulation; drug determination; drug effect; drug repositioning; gene expression; histology; liver cell carcinoma; liver function; male; mouse; nonhuman; oxidative stress; protein expression; protein targeting; signal transduction; tumor invasion; tumor suppressor gene

Citation Information

Scopus Citations: 38

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