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

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 antidiabet...

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Autores principales:	Amir Mohamed Abdelhamid, Sameh Saber, Mahmoud E. Youssef, Ahmed Gaafar Ahmed Gaafar, Hanan Eissa, Marwa A. Abd-Eldayem, Mohammed Alqarni, Gaber El-Saber Batiha, Ahmad J. Obaidullah, Mohamed Awad Shahien, Eman El-Ahwany, Noha A. Amin, Mohamed Ali Etman, Mohamed M.Y. Kaddah, Eslam E. Abd El-Fattah
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Hepatocellular carcinoma Emagliflozin/metformin Autophagy Apoptosis Angiogenesis Metastasis Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/243e31ff9d064d9ab4bb5a9d133137d8
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spelling	oai:doaj.org-article:243e31ff9d064d9ab4bb5a9d133137d82021-11-28T04:28:16ZEmpagliflozin adjunct with metformin for the inhibition of hepatocellular carcinoma progression: Emerging approach for new application0753-332210.1016/j.biopha.2021.112455https://doaj.org/article/243e31ff9d064d9ab4bb5a9d133137d82022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221012415https://doaj.org/toc/0753-3322Hepatocellular 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.Amir Mohamed AbdelhamidSameh SaberMahmoud E. YoussefAhmed Gaafar Ahmed GaafarHanan EissaMarwa A. Abd-EldayemMohammed AlqarniGaber El-Saber BatihaAhmad J. ObaidullahMohamed Awad ShahienEman El-AhwanyNoha A. AminMohamed Ali EtmanMohamed M.Y. KaddahEslam E. Abd El-FattahElsevierarticleHepatocellular carcinomaEmagliflozin/metforminAutophagyApoptosisAngiogenesisMetastasisTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 145, Iss , Pp 112455- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Hepatocellular carcinoma Emagliflozin/metformin Autophagy Apoptosis Angiogenesis Metastasis Therapeutics. Pharmacology RM1-950
spellingShingle	Hepatocellular carcinoma Emagliflozin/metformin Autophagy Apoptosis Angiogenesis Metastasis Therapeutics. Pharmacology RM1-950 Amir Mohamed Abdelhamid Sameh Saber Mahmoud E. Youssef Ahmed Gaafar Ahmed Gaafar Hanan Eissa Marwa A. Abd-Eldayem Mohammed Alqarni Gaber El-Saber Batiha Ahmad J. Obaidullah Mohamed Awad Shahien Eman El-Ahwany Noha A. Amin Mohamed Ali Etman Mohamed M.Y. Kaddah Eslam E. Abd El-Fattah Empagliflozin adjunct with metformin for the inhibition of hepatocellular carcinoma progression: Emerging approach for new application
description	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.
format	article
author	Amir Mohamed Abdelhamid Sameh Saber Mahmoud E. Youssef Ahmed Gaafar Ahmed Gaafar Hanan Eissa Marwa A. Abd-Eldayem Mohammed Alqarni Gaber El-Saber Batiha Ahmad J. Obaidullah Mohamed Awad Shahien Eman El-Ahwany Noha A. Amin Mohamed Ali Etman Mohamed M.Y. Kaddah Eslam E. Abd El-Fattah
author_facet	Amir Mohamed Abdelhamid Sameh Saber Mahmoud E. Youssef Ahmed Gaafar Ahmed Gaafar Hanan Eissa Marwa A. Abd-Eldayem Mohammed Alqarni Gaber El-Saber Batiha Ahmad J. Obaidullah Mohamed Awad Shahien Eman El-Ahwany Noha A. Amin Mohamed Ali Etman Mohamed M.Y. Kaddah Eslam E. Abd El-Fattah
author_sort	Amir Mohamed Abdelhamid
title	Empagliflozin adjunct with metformin for the inhibition of hepatocellular carcinoma progression: Emerging approach for new application
title_short	Empagliflozin adjunct with metformin for the inhibition of hepatocellular carcinoma progression: Emerging approach for new application
title_full	Empagliflozin adjunct with metformin for the inhibition of hepatocellular carcinoma progression: Emerging approach for new application
title_fullStr	Empagliflozin adjunct with metformin for the inhibition of hepatocellular carcinoma progression: Emerging approach for new application
title_full_unstemmed	Empagliflozin adjunct with metformin for the inhibition of hepatocellular carcinoma progression: Emerging approach for new application
title_sort	empagliflozin adjunct with metformin for the inhibition of hepatocellular carcinoma progression: emerging approach for new application
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/243e31ff9d064d9ab4bb5a9d133137d8
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Empagliflozin adjunct with metformin for the inhibition of hepatocellular carcinoma progression: Emerging approach for new application

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