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

// John Chun-Hao Chen 1, 2, * , Hui-Yen Chuang 1, * , Fei-Ting Hsu 1, * , Yi-Chen Chen 3 , Yi-Chun Chien 4 , Jeng-Jong Hwang 1, 5 1 Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan 2 Department of Radiation Oncology, Mackay Memorial Hospital, New Taipei City, Taiwan 3 Department of Radiology, National Taiwan University Hospital, Taipei, Taiwan 4 Department of Medical Imaging and Radiological Sciences, I-Shou University, Jiaosu Village, Kaohsiung, Taiwan 5 Biophotonics and Molecular Imaging Research Center, National Yang-Ming University, Taipei, Taiwan * These authors have contributed equally to this work Correspondence to: Jeng-Jong Hwang, email: jjhwang@ym.edu.tw Keywords: hepatocellular carcinoma, sorafenib, radiation, MEK/ERK/NF-κB signaling, molecular imaging Received: July 16, 2016      Accepted: October 28, 2016      Published: November 16, 2016 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.