Trichostatin A (TSA), a hydroxamate histone deacetylase inhibitor, is a compound that has been identified to induce anticancer activity. The aim of the present study was to investigate whether sorafenib, in combination with TSA, was able to augment the anticancer effects of TSA, identifying an optimum treatment time plan and the potential underlying molecular mechanisms involved in human hepatocellular carcinoma (HCC) in vitro. Huh7/nuclear factor-κB (NF-κB)-luc2 cells were treated with TSA or sorafenib alone, or sorafenib, prior to, in combination with or following TSA treatment. Huh7/NF-κB-luc2 cell viability following TSA treatment was determined using an MTT assay, and NF-κB activity was analyzed. In addition, the expression levels of NF-κB-regulated downstream effector proteins were assayed by western blotting. Inhibitors of mitogen-activated protein kinases (MAPKs), protein kinase B (AKT) and mutant inhibitor of NF-κBα (IκBαM) vectors were used to confirm the function of the NF-κB signal transduction pathways in response to the effects of sorafenib combined with TSA against HCC. The results of the present study indicated that pre-treatment with sorafenib followed by TSA inhibited the cell viability compared with other treatment modalities, and prevented TSA-induced extracellular-signal-regulated kinase (ERK)/NF-κB activity and expression of downstream effector proteins. It was further demonstrated that IκBαM vector sensitized Huh7/NF-κB-luc2 cells to TSA, thus it was possible to reverse TSA-induced NF-κB activity using PD98059, a MAPK/ERK kinase inhibitor. In conclusion, sorafenib pre-treatment may increase the efficacy of subsequent TSA treatment in HCC. Furthermore, sorafenib pre-treatment is hypothesized to sensitize HCC to TSA via the inhibition of the MEK/ERK/NF-κB signal transduction pathway.
ASJC Scopus subject areas
- Cancer Research
Chen, J. C. H., Chuang, H. Y., Liao, Y. J., Hsu, F. T., Chen, Y. C., Wang, W. H., & Hwang, J. J. (2019). Enhanced cytotoxicity of human hepatocellular carcinoma cells following pretreatment with sorafenib combined with trichostatin A. Oncology Letters, 17(1), 638-645. https://doi.org/10.3892/ol.2018.9582