Duan Shao-Feng, Zhang Meng-Meng, Dong Qian, Yang Bo, Liu Wei, Zhang Xin, Yu Hai-Lan, Zhang Shi-Hui, Khan Nazeer Hussain, Wu Dong-Dong, Zhang Xiao-Ju, Cen Juan
School of Pharmacy, Henan University, Kaifeng, Henan 475004, China.
Henan International Joint Laboratory for Chinese Medicine Efficacy, Henan University, Kaifeng, Henan 475004, China.
J Oncol. 2023 Mar 7;2023:8456852. doi: 10.1155/2023/8456852. eCollection 2023.
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 HS 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 HS-releasing donor) and morpholin-4-ium (4-methoxyphenyl)-morpholin-4-ylsulfanylidenesulfido-5-phosphane (GYY4137, a slow HS-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-3 (GSK-3), p--catenin, and also inhibited autophagy via the downregulation of the protein levels of p-Smad2, p-Smad3, and transforming growth factor- (TGF-) 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-3/-catenin and TGF-/Smad2/3 signaling pathways. HA-ADT and its derivatives may be developed as promising antitumor drugs.
肝细胞癌（HCC）是一种发病率高、死亡率高、治愈率低的疾病。透明质酸（HA）广泛应用于组织工程和药物递送。5-（4-羟基苯基）-3H-1,2-二硫醇-3-硫酮（ADT-OH）是常用的硫化氢（HS）供体之一。在我们之前的研究中，通过HA与ADT-OH偶联设计并合成了HA-ADT。在本研究中，与硫氢化钠（NaHS，一种快速释放HS的供体）和吗啉-4-鎓（4-甲氧基苯基）-吗啉-4-基硫代亚磺酰基硫代-5-膦（GYY4137，一种缓慢释放HS的供体）相比，HA-ADT对人肝癌细胞的增殖、迁移、侵袭和细胞周期具有更强的抑制作用。HA-ADT通过抑制磷酸化（p）-蛋白激酶B（PKB/AKT）、p-糖原合酶激酶-3（GSK-3）、p-β-连环蛋白的表达促进细胞凋亡，还通过下调人肝癌细胞中p-Smad2、p-Smad3和转化生长因子-β（TGF-β）的蛋白水平抑制自噬。此外，HA-ADT比NaHS和GYY4137更有效地抑制HCC异种移植瘤的生长。因此，HA-ADT可通过阻断AKT/GSK-3/β-连环蛋白和TGF-β/Smad2/3信号通路来抑制肝癌细胞的生长。HA-ADT及其衍生物有望开发成为有前景的抗肿瘤药物。
