Acetylation of α-tubulin by a Histone Deacetylase Inhibitor, Resminostat, Leads Synergistic Antitumor Effect with Docetaxel in Non-Small Cell Lung Cancer Models

Background: There is a growing body of clinical evidence to demonstrate that inhibition of histone deacetylase is effective in the treatment of various types of cancer. We examined whether acetylation of a non-histone protein α-tubulin was induced by resminostat and this acetylation exerts combination effects with docetaxel since α-tubulin was a target of docetaxel. Methods: The cytotoxicity of resminostat was evaluated in 11 human non-small cell lung cancer cell lines and the inhibitory activity of resminostat against histone deacetylase 6 was also determined. The stability of α-tubulin (the amount of polymerized and acetylated α-tubulin) was analyzed in NCI-H460 cells treated with resminostat and/or docetaxel. Caspase-3/7 activity was analyzed in NCI-H460, A549, NCI-H1975, and MOR/CPR cell lines treated with resminostat alone or in combination with docetaxel. The antitumor efficacies of resminostat and docetaxel were evaluated in xenograft mouse models. Results: Resminostat exhibited anti-proliferative activity in all 11 cell lines tested (IC50, 0.36-8.7 μmol/L) and also inhibited histone deacetylase 6 activities. The amounts of polymerized and acetylated α-tubulin and caspase-3/7 activity were increased by resminostat alone or the combination with docetaxel. This combination synergistically increased antitumor efficacy in all the tumor-bearing mice tested. Conclusions: These results demonstrate that the combination of resminostat and docetaxel offers a promising regimen in the treatment of non-small cell lung cancer.