Elucidation of the Molecular Mechanisms Underlying Sorafenib-Induced Hepatotoxicity

Abstract

Sorafenib is a small, orally-active multikinase inhibitor that is most frequently used for the management of renal cell carcinoma, hepatocellular carcinoma, and radioactive iodine-resistant thyroid carcinoma. However, recent reports have associated sorafenib with hepatotoxicity that can limit its clinical application, although the mechanism of hepatotoxicity is still to be elucidated. Thus, our study was designed to explore the molecular mechanisms underlying sorafenib-induced hepatotoxicity in an in vivo model. Twenty male adult Wistar rats were randomly placed into two groups; the first group received an oral dose of normal saline (vehicle), and the second received sorafenib (30 mg/kg) once daily for twenty-one consecutive days. After twenty-one days, liver tissues and blood samples were used for gene expression, protein expression, and biochemical analysis. Sorafenib treatment resulted in markedly increased levels of alanine aminotransferase and alkaline phosphatase, which indicate the presence of liver damage. Additionally, sorafenib administration induced the inflammatory and oxidative stress marker NF-κB-p65, while antioxidant enzymes were attenuated. Moreover, sorafenib caused upregulation of both gene and protein for the apoptotic markers cleaved Caspase-3, Bax, and Bid, and downregulation of the antiapoptotic protein Bcl-2. In conclusion, our findings suggest that sorafenib administration is associated with hepatotoxicity, which might be due to the activation of oxidative stress and apoptotic pathways.

Diosmin Alleviates Doxorubicin-Induced Liver Injury via Modulation of Oxidative Stress-Mediated Hepatic Inflammation and Apoptosis via NfkB and MAPK Pathway: A Preclinical Study

“…Immunoblot analysis was carried out as described previously [ 37 ]. Hepatic tissues were lysed, proteins were extracted, and equivalent amounts of proteins (0.02–0.05 mg) from control and treatment groups were loaded into 10–12% of SDS-PAGE for electrophoresis, followed by transfer to PVDF membranes.…”

Methyl Palmitate—A suitable adjuvant for Sorafenib therapy to reduce in vivo toxicity and to enhance anti‐cancer effects on hepatocellular carcinoma cells

“…Recent studies of sorafenib combination therapy with synthetic compounds showed a greater efficiency in reducing HCC and inducing apoptosis 6,8‐10 . The common mechanism of hepatotoxicity induction by chemotherapy and Sorafenib treatment is the enhancement of inflammation and oxidative stress which damages normal cells in liver 11,12 . A review article has highlighted the demand for combinational therapy for Sorafenib treatment which can increase the survival rate with minimized side effects 13 .…”

“…6,[8][9][10] The common mechanism of hepatotoxicity induction by chemotherapy and Sorafenib treatment is the enhancement of inflammation and oxidative stress which damages normal cells in liver. 11,12 A review article has highlighted the demand for combinational therapy for Sorafenib treatment which can increase the survival rate with minimized side effects. 13 Combination with natural polyphenolic compounds has potentiated the anti-cancer effects of Sorafenib treatment on human liver cancer cell line.…”

Sorafenib versus Lenvatinib Causes Stronger Oxidative Damage to Membrane Lipids in Noncancerous Tissues of the Thyroid, Liver, and Kidney: Effective Protection by Melatonin and Indole-3-Propionic Acid

“…However, it has been demonstrated in some studies that one of the mechanisms of this toxicity may be associated with reactive oxygen species (ROS) generation [ 13 , 14 ]. It has been also confirmed that sorafenib used in chronic treatment induces liver toxicity by activation of oxidative stress [ 15 ]. Moreover, evidence exists that antioxidant enzymes such as catalase and glutathione peroxidase (GPX) have diminished activities in sorafenib-treated animals [ 15 ].…”

“…It has been also confirmed that sorafenib used in chronic treatment induces liver toxicity by activation of oxidative stress [ 15 ]. Moreover, evidence exists that antioxidant enzymes such as catalase and glutathione peroxidase (GPX) have diminished activities in sorafenib-treated animals [ 15 ]. All of these observations directly indicate that both sorafenib and lenvatinib are strongly involved in the oxidative processes in the cell.…”