A Water-Soluble Hydrogen Sulfide Donor Suppresses the Growth of Hepatocellular Carcinoma via Inhibiting the AKT/GSK-3 β/ β-Catenin and TGF- β/Smad2/3 Signaling Pathways

Shao-Feng Duan; Meng-Meng Zhang; Qian Dong; Bo Yang; Wei Liu; Xin Zhang; Hai-Lan Yu; Shi-Hui Zhang; Nazeer Hussain Khan; Dong-Dong Wu; Xiao-Ju Zhang; Juan Cen

doi:10.1155/2023/8456852

A Water-Soluble Hydrogen Sulfide Donor Suppresses the Growth of Hepatocellular Carcinoma via Inhibiting the AKT/GSK-3 β/ β-Catenin and TGF- β/Smad2/3 Signaling Pathways

J Oncol. 2023 Mar 7:2023:8456852. doi: 10.1155/2023/8456852. eCollection 2023.

Authors

Shao-Feng Duan^{1

2}, Meng-Meng Zhang¹, Qian Dong¹, Bo Yang¹, Wei Liu¹, Xin Zhang¹, Hai-Lan Yu¹, Shi-Hui Zhang¹, Nazeer Hussain Khan³, Dong-Dong Wu³, Xiao-Ju Zhang⁴, Juan Cen⁵

Affiliations

¹ School of Pharmacy, Henan University, Kaifeng, Henan 475004, China.
² Henan International Joint Laboratory for Chinese Medicine Efficacy, Henan University, Kaifeng, Henan 475004, China.
³ Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China.
⁴ Department of Respiratory and Critical Care Medicine, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, Henan 450003, China.
⁵ Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University, Kaifeng, Henan 475001, China.

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.