Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase

Oncogene. 2004 Sep 23;23(44):7330-44. doi: 10.1038/sj.onc.1207995.


The antitumor activity of the sesquiterpene lactone parthenolide, an active ingredient of medicinal plants, is believed to be due to the inhibition of DNA binding of transcription factors NF-kappaB and STAT-3, reduction in MAP kinase activity and the generation of reactive oxygen. In this report, we show that parthenolide activates c-Jun N-terminal kinase (JNK), which is independent of inhibition of NF-kappaB DNA binding and generation of reactive oxygen species. Parthenolide reversed resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Cancer cells treated with a combination of TRAIL and parthenolide underwent massive typical apoptosis and atypical apoptosis involving the loss of plasma membrane integrity. JNK activity is necessary for the parthenolide-induced sensitization to TRAIL because a dominant-negative JNK or the JNK inhibitor SP600125 reduced TRAIL plus parthenolide-induced apoptosis. Parthenolide induced phosphorylation of Bid and increased TRAIL-dependent cleavage of Bid without affecting caspase 8 activities. Cytochrome c but not Smac/DIABLO was released from the mitochondria in cells treated with parthenolide alone. Parthenolide through JNK increased the TRAIL-mediated degradation of the antiapoptotic protein X-linked inhibitor of apoptosis (XIAP). Enhanced XIAP cleavage correlated with increased and prolonged caspase 3 activity and PARP cleavage, suggesting that the sensitization to TRAIL involves 'feed forward' activation of caspase 3. These results identify a new antitumor activity of parthenolide, which can be exploited to reverse resistance of cancer cells to TRAIL, particularly those with elevated XIAP levels.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis Regulatory Proteins
  • Breast Neoplasms
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / physiology*
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Membrane Glycoproteins / drug effects
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-kappa B / deficiency
  • NF-kappa B / genetics
  • Oxidative Stress / drug effects
  • Sesquiterpenes / pharmacology*
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha / drug effects
  • Tumor Necrosis Factor-alpha / physiology*


  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Membrane Glycoproteins
  • NF-kappa B
  • Sesquiterpenes
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tnfsf10 protein, mouse
  • Tumor Necrosis Factor-alpha
  • parthenolide
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases