Evodiamine induces tumor cell death through different pathways: apoptosis and necrosis

Acta Pharmacol Sin. 2004 Jan;25(1):83-9.


Aim: To study the different death pathways in human cervical cancer HeLa and melanoma A375-S2 cells initiated by evodiamine.

Methods: Viability of evodiamine-induced HeLa and A375-S2 cells was measured by MTT assay. Apoptotic cells with condensed or fragmented nuclei were visualized by Hoechst 33258 staining. Nucleosomal DNA fragmentation was assayed by agarose gel electrophoresis. Proportion of cell death through apoptotic and necrotic pathways was determined by LDH activity-based cytotoxicity assays. Cell cycle distribution was observed by flow cytometry.

Results: Evodiamine induced HeLa and A375-S2 cell death dose- and time-dependently. Caspase-3 and -8 were activated in apoptosis induced by evodiamine 15 micromol/L. However, over 24-h incubation of A375-S2 cells, evodiamine 15 micromol/L initiated necrosis related to p38 and ERK (extracellular signal-regulated kinases) activities. Evodiamine-induced HeLa cell death was preceded by an accumulation of cells at the G2/M phase of the cell cycle, but there was no significant effect of evodiamine on A375-S2 cell cycle.

Conclusion: Evodiamine induces caspase-3,8-dependent apoptosis in HeLa cells which is related to G2/M arrest of the cell cycle. On the other hand, in A375-S2 cells, evodiamine initiates caspase-3,8-mediated apoptosis at early stages and the induction of MAPK-mediated necrosis at later stages of cell culture.

MeSH terms

  • Apoptosis / drug effects*
  • Caspase 3
  • Caspase 8
  • Caspases / metabolism*
  • Cell Cycle
  • DNA Fragmentation
  • Dose-Response Relationship, Drug
  • Evodia / chemistry
  • HeLa Cells / metabolism
  • HeLa Cells / pathology
  • Humans
  • Melanoma / metabolism
  • Melanoma / pathology
  • Mitogen-Activated Protein Kinases / metabolism*
  • Necrosis
  • Plant Extracts / administration & dosage
  • Plant Extracts / isolation & purification
  • Plant Extracts / pharmacology*
  • Plants, Medicinal / chemistry
  • Quinazolines / administration & dosage
  • Quinazolines / isolation & purification
  • Quinazolines / pharmacology*
  • Time Factors
  • p38 Mitogen-Activated Protein Kinases


  • Plant Extracts
  • Quinazolines
  • evodiamine
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • CASP3 protein, human
  • CASP8 protein, human
  • Caspase 3
  • Caspase 8
  • Caspases