Empagliflozin adjunct with metformin for the inhibition of hepatocellular carcinoma progression: Emerging approach for new application

Theodor Bilharz Research Institute

Bibliographic Information

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

Journal: Biomedicine and Pharmacotherapy

Publisher: Elsevier Masson s.r.l.

Publication Date: January 2022

Volume / Issue: Volume 145

Article No.: 112455

ISSN: 7533322

DOI: 10.1016/j.biopha.2021.112455

Scopus: View on Scopus

PubMed: 34844106

Document Type: Article

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

Authors and Affiliations

Abdelhamid A.M., Department of Pharmacology, 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; Gaafar A.G.A., Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port Said University, Port Said, Egypt; Eissa H., Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Abd-Eldayem M.A., Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University, New Damietta, Egypt; Alqarni M., Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia; Batiha G.E.-S., Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, AlBeheira, Egypt; Obaidullah A.J., Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia; Shahien M.A., Department of Clinical Pharmacology, Faculty of Medicine, Damietta University, Damietta, 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; Etman M.A., Research and Development, Department of Drug Stability, Safe Pharma, Pharco Pharmaceuticals, Alexandria, Egypt; Kaddah M.M.Y., Pharmaceutical and Fermentation Industries Development Center, City of Scientific Research and Technological Applications, New Borg El-Arab, 21934, Alexandria, Egypt; Abd El-Fattah E.E., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt

Abstract

Hepatocellular carcinoma (HCC) is on the rise worldwide, and its incidence in diabetic patients is two to three times that of non-diabetics. Current therapeutic options fail to provide considerable survival benefits to patients with HCC. There is a strong possibility that the FDA-approved antidiabetic combination of empagliflozin and metformin could show complementary effects to control HCC progression. However, their multitarget effects have not yet been studied on HCC development. Therefore, the present study aims to evaluate the antitumorigenic activity of this combination in non-diabetic mice with diethylnitrosamine-induced HCC. Empagliflozin/metformin combination prolonged survival and improved histological features of mice livers. Additionally, Empagliflozin/metformin showed anti-inflammatory potential and relieved oxidative stress. On the one hand these effects are likely attributed to the ability of metformin to inactivate NF-κB in an AMPK-dependent mechanism and on the other hand to the ability of the empagliflozin to inhibit the MAPKs, p38 and ERK1/2. Empagliflozin also showed a less robust effect on AMPK than that of metformin. Moreover, empagliflozin enhanced the autophagy inducing activity of metformin. Furthermore, empagliflozin/metformin exhibited increased apoptotic potential. Consequently, empagliflozin augmented the antitumorigenic function of metformin by exerting better control of angiogenesis, and metastasis. To conclude, our findings suggest empagliflozin as an ideal adjunct to metformin for the inhibition of HCC progression. In addition, since the incidence of hypoglycemia is minimal due to insulin-independent mechanism of action of both treatments, empagliflozin/metformin could be a promising therapeutic modality for the management of diabetic patients with HCC; and even non diabetic ones. © 2021 The Authors

Keywords

Angiogenesis; Apoptosis; Autophagy; Emagliflozin/metformin; Hepatocellular carcinoma; Metastasis; Animals; Benzhydryl Compounds; Carcinoma, Hepatocellular; Disease Progression; Glucosides; Hypoglycemic Agents; Liver Neoplasms; MAP Kinase Kinase Kinases; Metformin; Mice; Neovascularization, Pathologic; NF-kappa B; Signal Transduction; Sodium-Glucose Transporter 2 Inhibitors; alanine aminotransferase; alkaline phosphatase; alpha fetoprotein; aspartate aminotransferase; diethylnitrosamine; empagliflozin; gamma glutamyltransferase; gelatinase A; hydroxymethylglutaryl coenzyme A reductase kinase; immunoglobulin enhancer binding protein; mitogen activated protein kinase; mitogen activated protein kinase p38; protein Bax; protein bcl 2; serine threonine protein kinase ULK1; sodium chloride; tissue inhibitor of metalloproteinase 1; transforming growth factor beta; tumor necrosis factor; vasculotropin; antidiabetic agent; benzhydryl derivative; glucoside; mitogen activated protein kinase kinase kinase; adult; alkaline phosphatase blood level; alpha fetoprotein blood level; aminotransferase blood level; AMPK signaling; animal experiment; animal model; animal tissue; antiinflammatory activity; antitumorigenic activity; Article; aspartate aminotransferase blood level; autophagy (cellular); cancer growth; cancer inhibition; cancer survival; controlled study; diabetic patient; diethylnitrosamine-induced hepatocarcinogenesis; gamma glutamyl transferase blood level; histopathology; hypoglycemia; incidence; liver cell carcinoma; liver weight; male; mouse; necroinflammation; nonhuman; oxidative stress; real time polymerase chain reaction; survival analysis; animal; disease exacerbation; drug effect; liver tumor; metabolism; neovascularization (pathology); pathology; pharmacology

Citation Information

Scopus Citations: 62

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