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Valproic acid overcomes transforming growth factor-β-mediated sorafenib resistance in hepatocellular carcinoma

Yasunobu Matsuda1, Toshifumi Wakai2, Masayuki Kubota3

  • 1Department of Medical Technology, Niigata University Graduate School of Health Sciences 2-746 Asahimachi-dori, Chuo-Ku, Niigata 951-8518, Japan.

International Journal of Clinical and Experimental Pathology
|May 13, 2014
PubMed

Insights

Transforming growth factor-beta (TGF-β) confers sorafenib resistance in hepatoma cells by activating ERK/AKT signaling. Combination therapy with valproic acid (VPA) overcomes this resistance, enhancing anti-tumor effects.

Area of Science:

  • Hepatocellular Carcinoma Research
  • Molecular Oncology
  • Drug Resistance Mechanisms

Background:

  • Sorafenib is a key treatment for hepatocellular carcinoma (HCC).
  • Sorafenib resistance is a significant clinical challenge, particularly in patients with chronic liver disease.
  • Growth factor signaling pathways are implicated in cancer progression and drug resistance.

Purpose of the Study:

  • To investigate the role of growth factors, specifically transforming growth factor-beta (TGF-β), in sorafenib resistance in hepatoma cells.
  • To identify potential combination therapies to overcome sorafenib resistance.

Main Methods:

  • Hepatoma cell lines (HepG2, PLC/PRF/5) were treated with TGF-β prior to sorafenib exposure.
  • Cell viability was assessed using trypan blue staining and Annexin V assays.
  • Western blotting was used to analyze signaling pathways, including ERK and AKT phosphorylation.
  • Combination treatments with sorafenib and VPA, celecoxib, or lovastatin were evaluated.

Main Results:

  • TGF-β significantly inhibited the cytotoxic effects of sorafenib (15-54% reduction).
  • TGF-β activated ERK and AKT signaling, pathways that sorafenib failed to suppress in sensitized cells.
  • Chemical inhibition of ERK and AKT rescued the anti-tumor effect of sorafenib.
  • Combination treatment with sorafenib and valproic acid (VPA) significantly suppressed phosphorylated ERK and AKT and increased cell death (3.7-5.7-fold).
  • Sorafenib-induced cell migration was suppressed by the sorafenib-VPA combination.

Conclusions:

  • TGF-β mediated sorafenib resistance in hepatoma cells through the activation of the ERK/AKT signaling pathway.
  • Combined treatment with VPA demonstrates potential as an effective strategy to overcome sorafenib resistance in HCC.
Keywords:
SorafenibTGF-βhepatocellular carcinoma

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