Cytotoxic effect of peroxisome proliferator fenofibrate on human HepG2 hepatoma cell line and relevant mechanisms.
The aim of this work was to investigate the effects of hypolipidemic agent fenofibrate (FF), a peroxisome proliferator (PP), on human HepG2 cells and to characterize the intracellular events involved. The results showed that, in contrast to the tumor-promoting effects in rodents, high FF concentrations induced human HepG2 cell death through a mechanism involving an increase in the levels of reactive oxygen species (ROS) and intracellular GSH depletion, which led, through mitochondrial dysfunction and perturbation of intracellular Ca(2+) homeostasis, to cell death. The nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR(alpha)) was expressed following FF treatment. The results suggest that, although long-term administration of PPs causes liver cancer in susceptible species (e.g., rodents), FF inhibits the growth of human HepG2 cells in a dose-related manner and oxidative stress was involved in this effect.
Jiao
Hong-li
HL
Department of Molecular and Cell Biology, Institute of Biophysics, The Chinese Academy of Sciences, Beijing, 100101, China.
Zhao
Bao-lu
BL
D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D011345:Fenofibrate / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D018570:Risk Assessment; D014157:Transcription Factors / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D020025:Peroxisome Proliferators; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D005978:Glutathione; D002118:Calcium; D011345:Fenofibrate