Combined inhibition of sonic Hedgehog signaling and histone deacetylase is an effective treatment for liver cancer

Abstract

Clinical trials have revealed that inhibition of sonic Hedgehog (SHH) signaling or histone deacetylase (HDAC) holds promise as a treatment for liver cancer. Based on our previous results, it was hypothesized that dual inhibition of SHH and HDAC may contribute to more efficient targeting of this disease. The effect of SHH inhibitor vismodegib as a single‑agent or in combination with HDAC inhibitor entinostat was evaluated by Cell Counting Kit‑8 (CCK‑8) and flow cytometric assays, as well as immunoblotting. The synergistic effect on cell viability was assessed by combination indexes. Ex vivo cultured liver cancer tissues from a patient were treated with vismodegib as a single‑agent or in combination with entinostat, and analyzed by histological and immunohistochemical methods. The results revealed that the dual use of the SHH inhibitor and the HDAC inhibitor effectively synergized to inhibit proliferation, and promote apoptosis in liver cancer cells. Furthermore, the effect of the combination of these drugs was confirmed in an ex vivo culture of human liver cancer tissue. Mechanistically, combined use of SHH and HDAC inhibitors resulted in significantly greater downregulation of SHH and PI3K/mTOR signaling. In conclusion, the combined use of SHH signaling and HDAC inhibitors may be an effective therapeutic strategy for liver cancer.