25-OCH₃-PPD induces the apoptosis of activated t-HSC/Cl-6 cells via c-FLIP-mediated NF-κB activation

• Published in: Chemico-biological interactions Vol. 194; no. 2-3; pp. 106 - 112
• Main Authors: Wu, Yan-ling, Wan, Ying, Jin, Xue-Jun, OuYang, Bing-Qing, Bai, Ting, Zhao, Yu-Qing, Nan, Ji-Xing
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 15.11.2011
• Subjects: actin; Animals; antioxidant activity; apoptosis; Apoptosis - drug effects; Blotting, Western; CASP8 and FADD-Like Apoptosis Regulating Protein - physiology; caspase-3; Cell Line; cell viability; fibrosis; Glutathione - metabolism; hepatocytes; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; leaves; Mice; muscles; necrosis; NF-kappa B - metabolism; Panax ginseng; Panax notoginseng; roots; Sapogenins - pharmacology; seeds; Signal Transduction; therapeutics; transcription factor NF-kappa B; transforming growth factor beta 1; triterpenoids; tumor necrosis factor-alpha
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2011.08.010

25-OCH₃-PPD is a dammarane-type triterpene sapogenin isolated from the roots, leaves and seeds of Panax notoginseng, which has shown anti-tumor effects in several human cancer lines. In this study, we evaluated the effects of 25-OCH₃-PPD on apoptosis of activated t-HSC/Cl-6 cells induced by tumor necrosis factor-α (TNF-α). The inhibitory effects of eleven compounds isolated from Panax ginseng and P. notoginseng were detected in activated t-HSC/Cl-6 cells. 25-OCH₃-PPD produced a significant inhibitory effect on activated t-HSC/Cl-6 cells. However, 25-OCH₃-PPD showed almost no effect on the cell viability of Chang liver cells, a type of normal human hepatic cell line. Therefore, we aimed to determine the anti-fibrotic potential of 25-OCH₃-PPD and to characterize the signal transduction pathways involved in activated HSCs. 25-OCH₃-PPD decreased the fibrosis markers, including α-smooth muscle actin (α-SMA), transforming growth factor β-1 (TGF-β1) and tissue inhibitors of metalloproteinases-1 (TIMP-1). 25-OCH₃-PPD elevated the level of cellular GSH in activated HSCs, which demonstrated that 25-OCH₃-PPD might inhibit HSC activation by its antioxidant capacity. Further analyses revealed that 25-OCH₃-PPD increased the levels of cleaved caspase-3, decreased the ratio of Bcl-2/Bax and the expression of survivin via c-FLIP-mediated NF-κB activation and shed light on the regulation of apoptosis. Therefore, 25-OCH₃-PPD may prove to be an excellent candidate agent for the therapy of hepatic fibrosis.