Rhein induces apoptosis in HL-60 cells via reactive oxygen species-independent mitochondrial death pathway

Arch Biochem Biophys. 2003 Oct 15;418(2):99-107. doi: 10.1016/j.abb.2003.08.004.


Rhein is an anthraquinone compound enriched in the rhizome of rhubarb, a traditional Chinese medicine herb showing anti-tumor promotion function. In this study, we first reported that rhein could induce apoptosis in human promyelocytic leukemia cells (HL-60), characterized by caspase activation, poly(ADP)ribose polymerase (PARP) cleavage, and DNA fragmentation. The efficacious induction of apoptosis was observed at 100 microM for 6h. Mechanistic analysis demonstrated that rhein induced the loss of mitochondrial membrane potential (DeltaPsi(m)), cytochrome c release from mitochondrion to cytosol, and cleavage of Bid protein. Rhein also induced generation of reactive oxygen species (ROS) and the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 kinase. However, these actions seem not to be associated with the apoptosis induction because antioxidants including N-acetyl cysteine (NAC), Tiron, and catalase did not block rhein-induced apoptosis, although they could block the generation of ROS and the phosphorylation of JNK and p38 kinase. Our data demonstrate that rhein induces apoptosis in HL-60 cells via a ROS-independent mitochondrial death pathway.

MeSH terms

  • Anthraquinones / pharmacology*
  • Apoptosis / drug effects*
  • BH3 Interacting Domain Death Agonist Protein
  • Carrier Proteins / metabolism
  • Caspase 3
  • Caspases / biosynthesis
  • Caspases / drug effects
  • Cytochromes c / metabolism
  • DNA Fragmentation / drug effects
  • DNA Fragmentation / physiology
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • HL-60 Cells / drug effects
  • HL-60 Cells / enzymology
  • HL-60 Cells / physiology
  • Humans
  • JNK Mitogen-Activated Protein Kinases*
  • MAP Kinase Kinase 4
  • Membrane Potentials / drug effects
  • Mitochondria / drug effects*
  • Mitochondria / enzymology
  • Mitochondria / metabolism*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Poly(ADP-ribose) Polymerases / metabolism
  • Reactive Oxygen Species / metabolism*


  • Anthraquinones
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Carrier Proteins
  • Reactive Oxygen Species
  • Cytochromes c
  • Poly(ADP-ribose) Polymerases
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • rhein