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

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          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.

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          Most cited references33

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          Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling.

          Although patients with advanced refractory solid tumors have poor prognosis, the clinical development of targeted protein kinase inhibitors offers hope for the future treatment of many cancers. In vivo and in vitro studies have shown that the oral multikinase inhibitor, sorafenib, inhibits tumor growth and disrupts tumor microvasculature through antiproliferative, antiangiogenic, and/or proapoptotic effects. Sorafenib has shown antitumor activity in phase II/III trials involving patients with advanced renal cell carcinoma and hepatocellular carcinoma. The multiple molecular targets of sorafenib (the serine/threonine kinase Raf and receptor tyrosine kinases) may explain its broad preclinical and clinical activity. This review highlights the antitumor activity of sorafenib across a variety of tumor types, including renal cell, hepatocellular, breast, and colorectal carcinomas in the preclinical setting. In particular, preclinical evidence that supports the different mechanisms of action of sorafenib is discussed.
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            Radiation-associated liver injury.

            The liver is a critically important organ that has numerous functions including the production of bile, metabolism of ingested nutrients, elimination of many waste products, glycogen storage, and plasma protein synthesis. The liver is often incidentally irradiated during radiation therapy (RT) for tumors in the upper- abdomen, right lower lung, distal esophagus, or during whole abdomen or whole body RT. This article describes the endpoints, time-course, and dose-volume effect of radiation on the liver. Published by Elsevier Inc.
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              Targeting transcription factor NF-kappaB to overcome chemoresistance and radioresistance in cancer therapy.

              Activation of transcription factor NF-kappaB is frequently encountered in tumor cells and contributes to aggressive tumor growth and resistance to chemotherapy and ionizing radiation during cancer treatment. Accumulating evidence over the last few years indicate that most chemotherapeutic agents and radiation therapy activate NF-kappaB in vitro and in vivo. Moreover, induction of chemoresistance and radioresistance is mediated through several genes regulated by NF-kappaB and inhibition of this transcription factor increases sensitivity of cancer cells to the apoptotic action of chemotherapeutic agents and to radiation exposure. This review explores the role of NF-kappaB and its regulated genes in resistance of tumor cells to chemotherapeutic agents and radiation and evaluates the importance of targeting NF-kappaB as a potential therapeutic approach to overcome chemoresistance and radioresistance for cancer treatment.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                20 December 2016
                16 November 2016
                : 7
                : 51
                : 85450-85463
                Affiliations
                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
                Author notes
                Correspondence to: Jeng-Jong Hwang, jjhwang@ 123456ym.edu.tw
                Article
                13398
                10.18632/oncotarget.13398
                5356748
                27863427
                6fed8a00-9006-43ed-ad1d-c20b4ffa74be
                Copyright: © 2016 Chen et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 16 July 2016
                : 28 October 2016
                Categories
                Research Paper

                Oncology & Radiotherapy
                hepatocellular carcinoma,sorafenib,radiation,mek/erk/nf-κb signaling,molecular imaging

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