Assessment of the main signaling pathways involved in the combined therapy of hepatocellular carcinoma using Sorafenib and NK cells in xenograft mice model

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Sorafenib is the only FDA approved drug for HCC patients, affecting patient survival by just a few months with significant toxicities in approximately half of HCC patients and the poor prognosis of these patients. Thus, the combination therapy with Sorafenib and Natural killer (NK) cells has been suggested, due to NK cells' distinct effectiveness against HCC. This research examined the main signaling pathways in HCC progression affected by Sorafenib or NK cells in combination or individual treatment. The xenograft model of HCC was created by implanting human HepG2 cells subcutaneously into the flank of 12 nude mice and then divided into four groups: Control, Sorafenib, NK cells, and Sorafenib plus NK cells. Four weeks post tumor implantation, the mice were euthanized, and the levels of liver and kidney enzymes were analysed for safety purposes. Quantitative real-time PCR analysis was used to measure the expression of key effector genes related to Sorafenib and NK cell functions with focused on the signaling pathways involved in the development of HCC. The levels of Aspartate aminotransferase (AST), Alanine transaminase (ALT), Blood urea nitrogen (BUN), and creatinine (Cr) in all groups remained in normal ranges. The expression levels of certain proliferative, anti-apoptotic factors were reduced in groups treated with either Sorafenib or NK cells only, but in combinational treated group showed no significant differences compared to control group. Also, the NK cell effector function related genes were upregulated in NK cell treated group, but inhibited in co administration of both NK cell and Sorafenib. Therefore, combining Sorafenib and NK cells at the prescribed dosage led to a decrease in the anti-cancer efficiency of both and may not be a successful option for HCC treatment.