Novel matrine derivative MD-1 attenuates hepatic fibrosis by inhibiting EGFR activation of hepatic stellate cells

• Published in: Protein & cell Vol. 7; no. 9; pp. 662 - 672
• Main Authors: Feng, Yi, Ying, Hai-yan, Qu, Ying, Cai, Xiao-bo, Xu, Ming-yi, Lu, Lun-gen
• Format: Journal Article
• Language: English
• Published: Beijing Higher Education Press 01.09.2016; Springer Nature B.V; Oxford University Press
• Subjects: Alkaloids - pharmacology; Animals; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Line; Cyclin D1 - metabolism; Developmental Biology; Dimethylnitrosamine - toxicity; EGFR; Enzyme Activation - drug effects; epidermal growth factor receptor; G1 Phase Cell Cycle Checkpoints - drug effects; hepatic fibrosis; hepatic stellate cell; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - pathology; Human Genetics; Life Sciences; Liver Cirrhosis - chemically induced; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver Cirrhosis - prevention & control; matrine derivative; Phosphorylation - drug effects; Protein Science; Proto-Oncogene Proteins c-akt - metabolism; Quinolizines - pharmacology; Rats; Receptor, Epidermal Growth Factor - metabolism; Research Article; signal transduction pathway; Stem Cells; 细胞周期蛋白D1; 细胞活化; 肝星状细胞; 肝纤维化; 苦参碱; 衍生物; 表皮生长因子受体; hepatic stellate cell; hepatic fibrosis; epidermal growth factor receptor; matrine derivative; signal transduction pathway
• ISSN: 1674-800X; 1674-8018
• DOI: 10.1007/s13238-016-0285-2

Matrine （MT）, the effective component of Sophora fla- vescens Air, has been shown to have anti-inflammation, immune-suppressive, anti-tumor, and anti-hepatic fibrosis activities. However, the pharmacological effects of MT still need to be strengthened due to its relatively low efficacy and short half-life. In the present study, we report a more effective thio derivative of MT, MD-1, and its inhibitory effects on the activation of hepatic stellate cells （HSCs） in both cell culture and animal models. Cytological experiments showed that MD-1 can inhibit the proliferation of HSC-T6 cells with a half-maximal inhibitory concentration （ICs0） of 62 pmollL. In addition, MD-1 more strongly inhibits the migration of HSC-T6 cells compared to MT and can more effectively induce G0/G1 arrest and apoptosis. Investigating the biological mechanisms underlying anti-hepatic fibrosis in the presence of MD-I, we found that MD-I can bind the epidermal growth factor receptor （EGFR） on the surface of HSC-T6 cells, which can further inhibit the phospho- rylaUon of EGFR and its downstream protein kinase B （Akt）, resulting in decreased expression of cyclin D1 and eventual inhibition of the activation of HSC-T6 cells. Furthermore, in rats with dimethylnitrosamine （DMN）- induced hepatic fibrosis, MD-1 slowed the development and progression of hepatic fibrosis, protecting hepatic parenchymal cells and improving hepatic functions. Therefore, MD-1 is a potential drug for anti-hepatic fibrosis.