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

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.

Naringin inhibits cisplatin resistance of ovarian cancer cells by inhibiting autophagy mediated by the TGF-β2/smad2 pathway

“…TGF-β could induce autophagy via the smad in pancreatic cancer ( 30 ). TGF-β/smad2 also activates autophagy in hepatocellular carcinoma ( 31 ). Some TCMs have also been found to regulate autophagy by blocking the TGF-β/smad related factors.…”

Advances in Foxp3+ regulatory T cells (Foxp3+ Treg) and key factors in digestive malignancies

“…Liu et al (95) has discovered that the Foxp3 promoter and CpG region are hypermethylated by NA (cytosine-5)-methyl transferase 1 (DNMT1), which can limit Foxp3+Treg function and negatively controls HCC progression. Moreover, Gong et al ( 96) also can confirme that Foxp3 exhibits oncogenic effects in HCC through in vitro and in vivo experiments, and Foxp3 regulates the TGF-b/smad3/4 pathway to recognize and directly or indirectly act on the Myc promoter region of oncogenes to inhibit oncogene expression; at the same time, the over-expression of Foxp3 could promote the increase of apoptotic marker Bax and expression of apoptosis inhibitor p53, which promote cancer cell apoptosis (97,98).…”

Therapeutic Potential of Hydrogen Sulfide in Ischemia and Reperfusion Injury

“…A long-term sustained-release H2S system, DATS-MSN, has recently been developed to preserve donor hearts and prevent myocardial I/R injury [13,26]. As a sustained-release H2S donor, 5-(4-hydroxyphenyl)-3H-1,2-dithiol-3-thione (ADT) plays a therapeutic role in the blood vessels, kidneys, liver, and intestines [27][28][29][30]. Zofenopril, a thiol-containing angiotensin-converting enzyme (ACE) inhibitor, has been identified as a novel H2S donor with significant clinical value in treating cardiovascular diseases [18].…”