Intracellular glutathione depletion by oridonin leads to apoptosis in hepatic stellate cells

Liang Mou Kuo, Chan Yen Kuo, Chen Yu Lin, Min Fa Hung, Jiann Jong Shen, Tsong Long Hwang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

94 Scopus citations

Abstract

Proliferation of hepatic stellate cells (HSCs) plays a key role in the pathogenesis of liver fibrosis. Induction of HSC apoptosis by natural products is considered an effective strategy for treating liver fibrosis. Herein, the apoptotic effects of 7,20-epoxy-ent-kaurane (oridonin), a diterpenoid isolated from Rabdosia rubescens, and its underlying mechanisms were investigated in rat HSC cell line, HSC-T6. We found that oridonin inhibited cell viability of HSC-T6 in a concentration-dependent manner. Oridonin induced a reduction in mitochondrial membrane potential and increases in caspase 3 activation, subG1 phase, and DNA fragmentation. These apoptotic effects of oridonin were completely reversed by thiol antioxidants, N-acetylcysteine (NAC) and glutathione monoethyl ester. Moreover, oridonin increased production of reactive oxygen species (ROS), which was also inhibited by NAC. Significantly, oridonin reduced intracellular glutathione (GSH) level in a concentrationand time-dependent fashion. Additionally, oridonin induced phosphorylations of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK). NAC prevented the activation of MAPKs in oridonin-induced cells. However, selective inhibitors of MAPKs failed to alter oridonin-induced cell death. In summary, these results demonstrate that induction of apoptosis in HSC-T6 by oridonin is associated with a decrease in cellular GSH level and increase in ROS production.

Original languageEnglish
Pages (from-to)3327-3344
Number of pages18
JournalMolecules
Volume19
Issue number3
DOIs
StatePublished - 03 2014

Keywords

  • Apoptosis
  • Glutathione
  • Hepatic Stellate Cells
  • Oridonin
  • Reactive Oxygen Species

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