Rapid reactive oxygen species (ROS) generation induced by curcumin leads to caspase-dependent and -independent apoptosis in L929 cells

Free Radic Biol Med. 2008 Nov 15;45(10):1403-12. doi: 10.1016/j.freeradbiomed.2008.08.014. Epub 2008 Aug 16.


Evidence that curcumin may have anticancer activities has renewed interest in its potential to prevent and treat disease. In this study, we show that curcumin-mediated rapid generation of reactive oxygen species (ROS) leads to apoptosis by modulating different apoptotic pathways in mouse fibroblast L929 cells. We show for the first time that curcumin-induced rapid ROS generation causes the release of apoptosis inducing factor (AIF) from the mitochondria to the cytosol and nucleus, hence, leading to caspase 3-independent apoptosis. However, our studies also show that curcumin induces the release of cytochrome c from mitochondria, causing activation of caspase 3, and concomitant PARP cleavage, which is the hallmark of caspase-dependent apoptosis. Furthermore, curcumin-induced ROS generation leads to the induction of the proapoptotic protein p53 and its effector protein p21 and down-regulation of cell cycle regulatory proteins such as Rb and cyclin D1 and D3. Both glutathione (GSH) and N-acetylcysteine (NAC) pretreatment resulted in the complete inhibition of curcumin-induced ROS generation, AIF release from mitochondria, and caspase activation. Additionally, pretreatment of L929 cells with these antioxidants completely blocked the induction of p53-dependent p21 accumulation. In conclusion, our data show that in addition to caspase 3 activation, curcumin-induced rapid ROS generation leads to AIF release, and the activation of the caspase-independent apoptotic pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Antioxidants / pharmacology
  • Apoptosis / drug effects*
  • Caspase 3 / metabolism*
  • Caspase Inhibitors
  • Cell Cycle Proteins / biosynthesis
  • Cell Cycle Proteins / drug effects
  • Cell Line
  • Cell Survival / drug effects
  • Curcumin / pharmacology*
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cytochromes c / drug effects
  • Cytochromes c / metabolism
  • Dose-Response Relationship, Drug
  • Mice
  • Poly(ADP-ribose) Polymerases / metabolism
  • Reactive Oxygen Species / metabolism*
  • Time Factors
  • Tumor Suppressor Protein p53 / metabolism


  • Amino Acid Chloromethyl Ketones
  • Antioxidants
  • Caspase Inhibitors
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • Cytochromes c
  • Poly(ADP-ribose) Polymerases
  • Caspase 3
  • Curcumin