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.

TCF4/beta-Catenin Complex Activates Smo and Gli1 to Promote Migration and Proliferation of Hepatocellular Carcinoma Cells

“…Recently, microRNAs have been identified that they serve as signalling modulators in development of cancer, and play key roles in HCC cell progression [34] . Previous studies indicated that Wnt and Hh signalling plays key role during liver cancer cell development, migration, proliferation, and metastasis [22][23][24][25][26][27][28] . However, the molecular relationship between Wnt and Hh signalling in HCC to control cancer cell activity remains unclear.…”

“…Gli1 activates a gel-forming mucin, MUC5AC expressions, which in turn inhibit E-cadherin-dependent cell-cell adhesions while activating pancreatic ductal adenocarcinoma cell migration and invasion [14] . Previous studies reported that the inhibitors of Hh signalling pathway suppressed liver cancer cell proliferation and invasion [22] ; inhibition of sonic Hh signalling together with histone deacetylase effectively control liver cancer [23] . Activation of Wnt/ β-catenin and macrophage was observed as key steps of liver cancer development [24] .…”

Anti-tumor Effect of Hedgehog Signaling Inhibitor, Vismodegib, on Castration-resistant Prostate Cancer

“…Previous studies have reported that vismodegib induces apoptosis in several kinds of cancers (7,8,16) including PC (7). However, it is not clear whether induction of apoptosis occurs by an intrinsic or extrinsic pathway.…”

Exploration of an Prognostic Signature Related to Endoplasmic Reticulum Stress in Colorectal Adenocarcinoma and Their Response Targeting Immunotherapy

“…SHH is relatively static in adult mammalian tissues, and abnormal activation of SHH signaling is associated with the occurrence and development of a variety of tumors, such as skin, 31 liver, 32 breast, 33 and lung cancer. 34 The involvement of SHH signaling in the occurrence of colon cancer may be related to the high expression of ALKAL1, which is indirectly involved in the invasion and metastasis of colon cancer.…”