Sorafenib pretreatment enhances radiotherapy through targeting MEK/ERK/NF-κB pathway in human hepatocellular carcinoma-bearing mouse model

Abstract

Patients with unresectable hepatocellular carcinoma (HCC) usually have poor prognosis because current monotherapy including surgery, chemotherapy and radiotherapy (RT) are not effective. Combination therapy may be effective to overcome this clinical problem. Here, we proposed the combination of sorafenib and RT, which have been applied in HCC treatment, could improve the treatment outcome of HCC. Our previous study showed that sorafenib could suppress the expression of NF-κB which is related to the chemo- and radio-resistance. Nevertheless, the expression of NF-κB is oscillatory and is affected by the treatments. Thus, understanding the oscillation of NF-κB expression would be beneficial for determining the optimal treatment schedule in combination therapy. Here established Huh7/NF-κB-tk-luc2/rfp cell line, in which NF-κB indicates a NF-κB promoter, was utilized to noninvasively monitor the expression of NF-κB overtime in vitro and in vivo. The results show that pretreatment of sorafenib with RT suppresses the expressions of NF-κB and its downstream proteins induced by radiation through downregulation of phosphorylated extracellular signal-regulated kinase (pERK) most significantly compared with other treatment schedules. The results were further verified with Western blotting, EMSA, and NF-κB molecular imaging. These findings suggest that pretreatment of sorafenib with RT may be the ideal treatment schedule for the treatment of HCC.

Amentoflavone Inhibits Hepatocellular Carcinoma Progression Through Blockage of ERK/NF-ĸB Activation

“…Vorinostat, a histone deacetylase inhibitor, and radiation both inhibit tumor growth, while triggering ERK/NF-ĸB signaling in Huh7 HCC cells in vitro and in vivo. Moreover, blockage of ERK/NF-ĸB signaling sensitizes HCC to vorinostat or radiation (10,11). Inhibitors of ERK/NF-ĸB signaling have the potential to act as a new agent offering benefits for patients with HCC.…”

Synergistic antitumor activity of low-dose c-Met tyrosine kinase inhibitor and sorafenib on human non-small cell lung cancer cells

“…However, the phosphorylation of ERK was not significantly blocked by the combined treatment, compared with treatment with a low dose of Sorafenib. Sorafenib may exerts its effects on ERK via the Ras/Raf/MEK/ERK signaling pathway (45), which may account for the similar levels of phosphorylated ERK observed between the groups treated with Sorafenib.…”

Radiotherapy and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors in Renal Cancer

“…Radiation, however, also induces NF-κB activity via ERK phosphorylation and results in upregulation of NF-κB-related proteins. Sorafenib has been proven to inhibit both endogenous and radiation-induced NF-κB activity and circumvents the development of radioresistance in HCC [31]. Accordingly, the combination of sorafenib with RT could provide better tumor growth control than monotherapy.…”