Intracellular regulation of evodiamine-induced A375-S2 cell death

Biol Pharm Bull. 2003 Nov;26(11):1543-7. doi: 10.1248/bpb.26.1543.


We have reported that in A375-S2 cells, evodiamine isolated from Evodia rutaecarpa induces cell death of human melanoma, A375-S2, through two distinct pathways: apoptosis and necrosis. In the present study, we further demonstrate two different mechanisms by which evodiamine induces apoptosis and necrosis. Although caspase-1 and -10 inhibitors failed to block cell death, pan-caspase inhibitor and caspase-3, -8, and -9 inhibitors had marked inhibitory effects on apoptosis induced by 15 microM evodiamine. Furthermore, evodiamine-induced activation of caspase-3 resulted in the down-regulation of anti-apoptotic Bcl-2 expression and up-regulation of proapoptotic Bax expression. After 24 h incubation with evodiamine, no caspase inhibitor had any influence on cell death, but p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580) attenuated cell death; in contrast, extracellular signal-regulated protein kinase (ERK) MAPK inhibitor (PD98059) augmented cell death, as was further confirmed by cotreatment with SB203580 or PD98059 and pan-caspase inhibitor. Moreover, evodiamine increased the phosphorylation of p38 and decreased the expression and phosphorylation of ERK in caspase-independent necrosis. Consequently, evodiamine induced the caspase- and Bax-mediated apoptosis at an early stage, but, initiated MAPKs-dependent necrosis at a later stage.

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Caspases / metabolism
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Evodia
  • Humans
  • Intracellular Fluid / drug effects*
  • Intracellular Fluid / physiology
  • Plant Extracts / pharmacology*
  • Quinazolines / pharmacology*


  • Enzyme Inhibitors
  • Plant Extracts
  • Quinazolines
  • evodiamine
  • Caspases