The STAT3 inhibitor S3I-201 suppresses fibrogenesis and angiogenesis in liver fibrosis

• Published in: Laboratory investigation Vol. 98; no. 12; pp. 1600 - 1613
• Main Authors: Wang, Zhuo, Li, Jia'an, Xiao, Wen'ang, Long, Jiafu, Zhang, Hongmin
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.12.2018; Nature Publishing Group US; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/2; 13/31; 13/51; 13/95; 14/19; 631/154/556; 64/60; 692/699/1503/1607/1605; 82/29; 82/80; 96/21; Actin; AKT protein; Aminosalicylic Acids - pharmacology; Aminosalicylic Acids - therapeutic use; Angiogenesis; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Benzenesulfonates - pharmacology; Benzenesulfonates - therapeutic use; Bile; Carbon tetrachloride; Cell cycle; Cell Line; Cell proliferation; Collagen (type I); Deoxyribonucleic acid; Dimerization; DNA; Drug Synergism; Fibrosis; Hepatic Stellate Cells - drug effects; Humans; Inhibitors; Laboratory Medicine; Liver; Liver cancer; Liver Cirrhosis - prevention & control; Male; Medicine; Medicine & Public Health; Mice, Inbred BALB C; Neovascularization, Physiologic - drug effects; Organic chemistry; Pathology; Phosphorylation; Primary Cell Culture; Receptor, Transforming Growth Factor-beta Type II - metabolism; Smad2 protein; Smad3 protein; Sorafenib - pharmacology; Stat3 protein; STAT3 Transcription Factor - antagonists & inhibitors; Stellate cells; Synergistic effect; Tissue inhibitor of metalloproteinase 1; Transcription; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0023-6837; 1530-0307; 1530-0307
• DOI: 10.1038/s41374-018-0127-3

Liver fibrosis is a common pathological response to chronic hepatic injury. STAT3 is actively involved in the fibrogenesis and angiogenesis seen in liver fibrosis. S3I-201 (NSC 74859) is a chemical inhibitor of STAT3 activity, which blocks the dimerization of STAT3, STAT3-DNA binding and transcription activity. This study evaluated the effects of S3I-201 against liver fibrosis. S3I-201 inhibited the proliferation, migration, and actin filament formation in primary human hepatic stellate cells (HSCs), as well as the expression of α-SMA, collagen I and TIMP1 in both primary HSC and in a CCl4-induced fibrosis mouse model. S3I-201 induced both apoptosis and cell cycle arrest in the HSC cell line (LX-2). S3I-201 inhibited the expression of fibrogenesis factors TGFβ1 and TGFβRII, as well as the downstream phosphorylation of Smad2, Smad3, Akt and ERK induced by TGFβ1. In addition to fibrogenesis, both in vitro and in vivo assays showed that S3I-201 inhibited angiogenesis through expression suppression of VEGF and VEGFR2. Moreover, S3I-201 also had a synergistic effect with sorafenib, an FDA approved liver cancer drug, in the proliferation, apoptosis, angiogenesis and fibrogenesis of HSC. S3I-201 suppressed liver fibrosis through multiple mechanisms, and combined with sorafenib, S3I-201 could be a potentially effective antifibrotic agent. S3I-201, a chemical inhibitor of the transcription factor STAT3, suppresses liver fibrogenesis and angiogenesis through multiple mechanisms both in vitro and in vivo. Moreover, S3I-201 and sorafenib, an FDA-approved multikinase inhibitor, function synergistically in suppressing fibrogenesis and angiogenesis of human hepatic stellate cells, indicating high potential for liver fibrosis treatment.