Enhanced Cytotoxicity of Sorafenib in Hepatocellular Carcinoma through Synergistic Combination with Naringenin: A Molecular and Cellular Perspective

The most prevalent kind of liver tumor is hepatocellular carcinoma (HCC). Sorafenib is an efficient multikinase inhibitor used for treatment of HCC. However, the expensive cost and severe side effects of sorafenib limit its therapeutic potential. Therefore, the use of combination therapies to increase survival is advised. Naringenin is a naturally occurring flavonoid that has anti-inflammation properties and has been utilized for many years as a powerful antioxidant. Hence, this research objective is to study the ability of naringenin to increase the sensitivity of HepG2 cells towards sorafenib. Using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test, the damaging effects of naringenin and sorafenib on HepG2 cells were assessed. In the present research, HepG2 cells were separated into 4 groups; control group, group given sorafenib treatment in its IC50 conc (4.3 μM), group treated with naringenin in sub-lethal dose ¼ IC50 (7.25 μM) and combination group. The co-administration of naringenin and sorafenib had more deleterious effects on cell viability than does either drug alone. Expression variations of genes associated with angiogenesis and apoptosis (VEGF-a, TP53, caspase-8 and MAP3K5) were examined using quantitative real-time PCR. Compared with single drug therapy, sorafenib/naringenin combination therapy showed higher inhibitory effects on VEGF-A and enhancing effects on TP53, Capase-8 and MAP3K5. Together, the present study results suggest that low concentration of naringenin enhances the HepG2 cells sensitivity towards sorafenib alone. For naringenin to be used therapeutically in different types of cancer, more in vivo and in vitro studies on the dosage and duration of naringenin use are needed.