Histone Deacetylase 6 Inhibitor 5-Phenylcarbamoylpentyl Selenocyanide (SelSA) Suppresses Hepatocellular Carcinoma by Downregulating Phosphorylation of the Extracellular Signal-Regulated Kinase 1/2 Pathway

Abstract

Histone deacetylase 6 (HDAC6) enzyme plays a crucial role in a variety of cellular processes related to cancer, and inhibition of HDAC6 is emerging as an effective strategy for cancer treatment. Although several hydroxamate-based HDAC6 inhibitors showed promising anticancer activities, the intrinsic defects such as poor selectivity, stability, and pharmacokinetics limited their application. In this study, a potent selenocyanide-bearing HDAC6 inhibitor, 5-phenylcarbamoylpentyl selenocyanide (SelSA), was evaluated for its antihepatocellular carcinoma (HCC) activity and further explored for its antitumor mechanisms. In vitro studies demonstrated that SelSA exhibited excellent antiproliferative activity against three HCC cells HepG2 (2.3 ± 0.29 μM), Huh7 (0.83 ± 0.48 μM), and LM3 (2.6 ± 0.24 μM). Further studies indicated that SelSA could downregulate the expression of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, inhibit the growth, invasion, and migration of Huh7 cells, and promote their apoptosis. Moreover, SelSA significantly suppressed tumor growth in Huh7 xenograft mouse models. Our findings suggest that SelSA could be a potential therapeutic agent for HCC.