Synergistic Effects of Ellagic Acid and Sorafenib on Hepatocytes and Mitochondria Isolated from a Hepatocellular Carcinoma Rat Model

Abstract

Introduction

Hepatocellular carcinoma (HCC) is one of the deadliest and most common cancers in humans worldwide. Today, common treatment options for HCC are not effective. The synergistic relationship between compounds of natural origin and the drugs used in the treatment of cancer has been described. Ellagic acid (EA) as a compound of natural origin induces cell death in various cancer cell lines. Aim: The aim of this study was to investigate the effects of the alone or combination of EA and sorafenib (SOR) on HCC hepatocytes viability and apoptosis signaling both in vitro and in vivo. Methods: The synergistic effects of EA and SOR were tested in an HCC rat model. This was followed by cellular and mitochondrial parameters. Results: Results showed that SOR and EA applied alone or in combination increased the reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and cytochrome c release in the mitochondria only from the HCC hepatocytes group. Furthermore, SOR and EA applied alone or in combination increased the caspase-3 activity and decreased the hepatocyte viability only on the HCC group. Conclusions: We showed for the first time that EA and SOR are effective on the HCC rat model through mitochondria and hepatocytes targeting.

Acknowledgments

The authors acknowledge the Medical University of Alborz for providing access to the resources necessary for the completion of this study (1397-03-00-2092).

Authors’ contributions

ES and AS conceived and planned the study. ES, MS, and AS carried out the experiments. ES and MS processed the experimental data. ES performed the analysis and designed the Figures. ES, MS, and AS drafted the manuscript. All authors have read the manuscript, provided input for finalization, and approved the final version.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Experimental work was funded by Alborz University of Medical Sciences, Karaj, Iran [1397-03-00-2092].