Exp Mol Med.  2012 Jul;44(7):448-456.

Parthenolide-induced apoptosis of hepatic stellate cells and anti-fibrotic effects in an in vivo rat model

• Kim IH
• Kim SW
• Kim SH
• Lee SO
• Lee ST
• Kim DG
• Lee MJ
• Park WH

Abstract

Parthenolide (PT), a sesquiterpene lactone derived from the plant feverfew, has pro-apoptotic activity in a number of cancer cell types. We assessed whether PT induces the apoptosis of hepatic stellate cells (HCSs) and examined its effects on hepatic fibrosis in an in vivo model. The effects of PT on rat HSCs were investigated in relation to cell growth inhibition, apoptosis, NF-kappaB binding activity, intracellular reactive oxygen species (ROS) generation, and glutathione (GSH) levels. In addition, the anti-fibrotic effects of PT were investigated in a thioacetamide-treated rat model. PT induced growth inhibition and apoptosis in HSCs, as evidenced by cell growth inhibition and apoptosis assays. PT increased the expression of Bax proteins during apoptosis, but decreased the expression of Bcl-2 and Bcl-XL proteins. PT also induced a reduction in mitochondrial membrane potential, poly(ADP-ribose) polymerase cleavage, and caspase-3 activation. PT inhibited TNF-alpha-stimulated NF-kappaB binding activity in HSCs. The pro-apoptotic activity of PT in HSCs was associated with increased intracellular oxidative stress as evidenced by increased intracellular ROS levels and depleted intracellular GSH levels. Furthermore, PT ameliorated hepatic fibrosis significantly in a thioacetamide-treated rat model. In conclusion, PT exhibited pro-apoptotic effects in rat HSCs and ameliorated hepatic fibrosis in a thioacetamide-induced rat model.

Keyword

apoptosis; hepatic stellate cells; liver cirrhosis; parthenolide; reactive oxygen species; thioacetamide

MeSH Terms

Animals
Apoptosis/*drug effects
Gene Expression/drug effects
Hepatic Stellate Cells/*drug effects
Humans
Liver Cirrhosis/chemically induced/*drug therapy
Membrane Potential, Mitochondrial/drug effects
NF-kappa B/metabolism
Oxidative Stress/drug effects
Rats
Reactive Oxygen Species/metabolism
Sesquiterpenes/*administration & dosage
Thioacetamide/toxicity
Tumor Necrosis Factor-alpha/metabolism
bcl-2-Associated X Protein/metabolism
bcl-X Protein/metabolism