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

Fei Ting Hsu, Y. U Chang Liu, I. Tsang Chiang, Ren Shyan Liu, Hsin Ell Wang, Wuu Jyh Lin, Jeng Jong Hwang

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)177-188
Number of pages12
JournalInternational Journal of Oncology
Volume45
Issue number1
DOIs
Publication statusPublished - 2014
Externally publishedYes

Fingerprint

Hepatocellular Carcinoma
Molecular Imaging
sorafenib
vorinostat
Histone Deacetylase Inhibitors
Thymidine Kinase
Response Elements
Electrophoretic Mobility Shift Assay
DNA Fragmentation
Luciferases
Reporter Genes
Nude Mice
Cell Survival
B-Lymphocytes
Western Blotting
Apoptosis
Light
Cell Line
Survival

Keywords

  • Hepatocellular carcinoma
  • NF-κB
  • SAHA
  • Sorafenib
  • Vorinostat

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sorafenib increases efficacy of vorinostat against human hepatocellular carcinoma through transduction inhibition of vorinostat-induced ERK/NF-κB signaling. / Hsu, Fei Ting; Liu, Y. U Chang; Chiang, I. Tsang; Liu, Ren Shyan; Wang, Hsin Ell; Lin, Wuu Jyh; Hwang, Jeng Jong.

In: International Journal of Oncology, Vol. 45, No. 1, 2014, p. 177-188.

Research output: Contribution to journalArticle

Hsu, Fei Ting ; Liu, Y. U Chang ; Chiang, I. Tsang ; Liu, Ren Shyan ; Wang, Hsin Ell ; Lin, Wuu Jyh ; Hwang, Jeng Jong. / Sorafenib increases efficacy of vorinostat against human hepatocellular carcinoma through transduction inhibition of vorinostat-induced ERK/NF-κB signaling. In: International Journal of Oncology. 2014 ; Vol. 45, No. 1. pp. 177-188.
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