A Water-Soluble Hydrogen Sulfide Donor Suppresses the Growth of Hepatocellular Carcinoma via Inhibiting the AKT/GSK-3β/β-Catenin and TGF-β/Smad2/3 Signaling Pathways
Shaofeng Duan, Mengmeng Zhang, Qian Dong, Bo Yang, Wei Liu, Xin Zhang, Xin Zhang, Hailan Yu, Shihui Zhang, Nazeer Hussain Khan, Dongdong Wu, Xiaoju Zhang, Xiaoju Zhang, Juan Cen
Abstract
Hepatocellular carcinoma (HCC) is a disease with high morbidity, high mortality, and low cure rate. Hyaluronic acid (HA) is widely adopted in tissue engineering and drug delivery. 5-(4-Hydroxyphenyl)-3H-1, 2-dithiol-3-thione (ADT-OH) is one of commonly used H2S donors. In our previous study, HA-ADT was designed and synthesized via coupling of HA and ADT-OH. In this study, compared with sodium hydrosulfide (NaHS, a fast H2S-releasing donor) and morpholin-4-ium (4-methoxyphenyl)-morpholin-4-ylsulfanylidenesulfido-λ5-phosphane (GYY4137, a slow H2S-releasing donor), HA-ADT showed stronger inhibitory effect on the proliferation, migration, invasion, and cell cycle of human HCC cells. HA-ADT promoted apoptosis by suppressing the expressions of phospho (p)-protein kinase B (PKB/AKT), p‐glycogen synthase kinase‐3β (GSK-3β), p‐β‐catenin, and also inhibited autophagy via the downregulation of the protein levels of p‐Smad2, p‐Smad3, and transforming growth factor‐β (TGF‐β) in human HCC cells. Moreover, HA-ADT inhibited HCC xenograft tumor growth more effectively than both NaHS and GYY4137. Therefore, HA-ADT can suppress the growth of HCC cells by blocking the AKT/GSK-3β/β-catenin and TGF‐β/Smad2/3 signaling pathways. HA-ADT and its derivatives may be developed as promising antitumor drugs.