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.
Highlights
Hepatocellular carcinoma (HCC) is the fifth common malignancy worldwide and the mortality is ranked the third in cancer-related deaths
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 most significantly compared with other treatment schedules
To elucidate the underlying mechanism, the Huh7/NF-κB-tk-luc2/rfp cells were transfected with the IκBαM vector, to block the activation of NF-κB, and the NF-κB activity was monitored by bioluminescent imaging (BLI)
Summary
Hepatocellular carcinoma (HCC) is the fifth common malignancy worldwide and the mortality is ranked the third in cancer-related deaths. The incidence rate of HCC is continuously increasing [1, 2], in the East Asia where the rate exceeds 30 cases per 100,000 people per year [3]. The prognosis of patients with unresectable HCC is poor, and chemotherapy and radiotherapy (RT) could benefit little to these patients [4]. Various combinations of chemotherapy, targeted therapy, and RT have been investigated to achieve the better treatment outcome [5,6,7]. Neither suitable targets nor optimized treatment regimens for different stages of the disease yet identified, which are important for combining different therapies for HCC treatment
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