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International Journal of Oncology
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Print ISSN: 1019-6439 Online ISSN: 1791-2423
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Article

Sorafenib increases efficacy of vorinostat against human hepatocellular carcinoma through transduction inhibition of vorinostat-induced ERK/NF-κB signaling

  • Authors:
    • Fei-Ting Hsu
    • Yu-Chang Liu
    • I-Tsang Chiang
    • Ren-Shyan Liu
    • Hsin-Ell Wang
    • Wuu-Jyh Lin
    • Jeng-Jong Hwang
  • View Affiliations / Copyright

    Affiliations: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan, R.O.C., Department of Radiation Oncology, National Yang-Ming University Hospital, Yilan 260, Taiwan, R.O.C., Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan, R.O.C., Division of Radioisotope, Institute of Nuclear Energy Research, Taoyuan 32546, Taiwan, R.O.C.
  • Pages: 177-188
    |
    Published online on: May 6, 2014
       https://doi.org/10.3892/ijo.2014.2423
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Abstract

Sorafenib is effective for patients with advanced hepatocellular carcinoma (HCC) and particularly for those who are unsuitable to receive life-prolonging transarterial chemo­embolization. The survival benefit of sorafenib, however, is unsatisfactory. Vorinostat also known as suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase (HDAC) inhibitor with anti-HCC efficacy in preclinical studies. SAHA induces nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activity in vitro, which may lead to cancer cell progression and jeopardize cytotoxic effect of SAHA in HCC. The goal of this study was to investigate whether sorafenib enhances SAHA cytotoxicity against HCC through inhibition of SAHA-induced NF-κB activity. The human HCC cell line Huh7 transfected with dual reporter genes, luciferase (luc) and thymidine kinase (tk) with NF-κB response elements, was co-transfected with red fluorescent protein (rfp) gene for non-invasive molecular imaging to assess NF-κB activity and living cells simultaneously. Cell viability assay, DNA fragmentation, western blotting, electrophoretic mobility shift assay (EMSA) and multiple modalities of molecular imaging were used to assess the combination efficacy and mechanism of sorafenib and SAHA. The administration of high-dose SAHA (10 µM) with long treatment time (48 h) in vitro, and 25 mg/kg/day by gavage in HCC-bearing nude mice to induce NF-κB activity were performed. Sorafenib inhibited SAHA-induced NF-κB activity and the expression of NF-κB-regulated effector proteins while it increased the efficacy of SAHA against HCC both in vitro and in vivo. The mechanism of sorafenib to enhance SAHA efficacy on HCC is through the suppression of ERK/NF-κB pathway, which induces extrinsic and intrinsic apoptosis. Combination of sorafenib and SAHA may have the potential as new strategy against HCC.
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Copy and paste a formatted citation
Spandidos Publications style
Hsu F, Liu Y, Chiang I, Liu R, Wang H, Lin W and Hwang J: Sorafenib increases efficacy of vorinostat against human hepatocellular carcinoma through transduction inhibition of vorinostat-induced ERK/NF-κB signaling. Int J Oncol 45: 177-188, 2014.
APA
Hsu, F., Liu, Y., Chiang, I., Liu, R., Wang, H., Lin, W., & Hwang, J. (2014). Sorafenib increases efficacy of vorinostat against human hepatocellular carcinoma through transduction inhibition of vorinostat-induced ERK/NF-κB signaling. International Journal of Oncology, 45, 177-188. https://doi.org/10.3892/ijo.2014.2423
MLA
Hsu, F., Liu, Y., Chiang, I., Liu, R., Wang, H., Lin, W., Hwang, J."Sorafenib increases efficacy of vorinostat against human hepatocellular carcinoma through transduction inhibition of vorinostat-induced ERK/NF-κB signaling". International Journal of Oncology 45.1 (2014): 177-188.
Chicago
Hsu, F., Liu, Y., Chiang, I., Liu, R., Wang, H., Lin, W., Hwang, J."Sorafenib increases efficacy of vorinostat against human hepatocellular carcinoma through transduction inhibition of vorinostat-induced ERK/NF-κB signaling". International Journal of Oncology 45, no. 1 (2014): 177-188. https://doi.org/10.3892/ijo.2014.2423
Copy and paste a formatted citation
x
Spandidos Publications style
Hsu F, Liu Y, Chiang I, Liu R, Wang H, Lin W and Hwang J: Sorafenib increases efficacy of vorinostat against human hepatocellular carcinoma through transduction inhibition of vorinostat-induced ERK/NF-κB signaling. Int J Oncol 45: 177-188, 2014.
APA
Hsu, F., Liu, Y., Chiang, I., Liu, R., Wang, H., Lin, W., & Hwang, J. (2014). Sorafenib increases efficacy of vorinostat against human hepatocellular carcinoma through transduction inhibition of vorinostat-induced ERK/NF-κB signaling. International Journal of Oncology, 45, 177-188. https://doi.org/10.3892/ijo.2014.2423
MLA
Hsu, F., Liu, Y., Chiang, I., Liu, R., Wang, H., Lin, W., Hwang, J."Sorafenib increases efficacy of vorinostat against human hepatocellular carcinoma through transduction inhibition of vorinostat-induced ERK/NF-κB signaling". International Journal of Oncology 45.1 (2014): 177-188.
Chicago
Hsu, F., Liu, Y., Chiang, I., Liu, R., Wang, H., Lin, W., Hwang, J."Sorafenib increases efficacy of vorinostat against human hepatocellular carcinoma through transduction inhibition of vorinostat-induced ERK/NF-κB signaling". International Journal of Oncology 45, no. 1 (2014): 177-188. https://doi.org/10.3892/ijo.2014.2423
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