Two distinct modes of cell death induced by doxorubicin: apoptosis and cell death through mitotic catastrophe accompanied by senescence-like phenotype

Oncogene. 2005 Jul 14;24(30):4765-77. doi: 10.1038/sj.onc.1208627.


Chronic exposure of many human hepatoma cell lines to a low dose (LD) of doxorubicin induced a senescence-like phenotype (SLP) accompanied by enlargement of cells and increased senescence-associated beta-galactosidase activity. LD doxorubicin-induced SLP was preceded by multinucleation and downregulation of multiple proteins with mitotic checkpoint function, including CENP-A, Mad2, BubR1, and Chk1. LD doxorubicin-treated cells eventually underwent cell death through mitotic catastrophe. When we investigated whether LD doxorubicin-induced cell death shares biochemical characteristics with high dose (HD) doxorubicin-induced apoptosis in Huh-7 cells, we observed that externalization of phosphatidyl serine and release of mitochondrial cytochrome c into the cytosol was associated with both types of cell death. However, propidium iodide exclusion assays showed that membrane integrity was lost in the initial phase of LD doxorubicin-induced cell death through mitotic catastrophe, whereas it was lost during the late phase of HD doxorubicin-induced apoptosis. Furthermore, HD doxorubicin-induced apoptosis but not LD doxorubicin-induced mitotic catastrophe led to transient activation of NF-kappaB and strong, sustained activations of p38, c-Jun N-terminal kinase, and caspases. Collectively, these results indicate that different doses of doxorubicin activate different regulatory mechanisms to induce either apoptosis or cell death through mitotic catastrophe.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Caspases / metabolism
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Membrane Permeability / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cellular Senescence / drug effects*
  • Cytochromes c / metabolism
  • DNA / metabolism
  • Down-Regulation
  • Doxorubicin / pharmacology*
  • Enzyme Activation / drug effects
  • Humans
  • Kinetics
  • Lamin Type B / metabolism
  • Microscopy, Electron, Transmission
  • Mitochondria / metabolism
  • Mitosis / drug effects*
  • Models, Biological
  • NF-kappa B / metabolism
  • Phenotype
  • Signal Transduction / drug effects
  • Spindle Apparatus / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Lamin Type B
  • NF-kappa B
  • Doxorubicin
  • Cytochromes c
  • DNA
  • p38 Mitogen-Activated Protein Kinases
  • Caspases