Cardiac glycosides exert anticancer effects by inducing immunogenic cell death

Sci Transl Med. 2012 Jul 18;4(143):143ra99. doi: 10.1126/scitranslmed.3003807.


Some successful chemotherapeutics, notably anthracyclines and oxaliplatin, induce a type of cell stress and death that is immunogenic, hence converting the patient's dying cancer cells into a vaccine that stimulates antitumor immune responses. By means of a fluorescence microscopy platform that allows for the automated detection of the biochemical hallmarks of such a peculiar cell death modality, we identified cardiac glycosides (CGs) as exceptionally efficient inducers of immunogenic cell death, an effect that was associated with the inhibition of the plasma membrane Na(+)- and K(+)-dependent adenosine triphosphatase (Na(+)/K(+)-ATPase). CGs exacerbated the antineoplastic effects of DNA-damaging agents in immunocompetent but not immunodeficient mice. Moreover, cancer cells succumbing to a combination of chemotherapy plus CGs could vaccinate syngeneic mice against a subsequent challenge with living cells of the same type. Finally, retrospective clinical analyses revealed that the administration of the CG digoxin during chemotherapy had a positive impact on overall survival in cohorts of breast, colorectal, head and neck, and hepatocellular carcinoma patients, especially when they were treated with agents other than anthracyclines and oxaliplatin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthracyclines / pharmacology
  • Anthracyclines / therapeutic use
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use*
  • Biosensing Techniques
  • Cardiac Glycosides / pharmacology*
  • Cardiac Glycosides / therapeutic use*
  • Cell Line, Tumor
  • Digoxin / pharmacology
  • Digoxin / therapeutic use
  • Humans
  • Mice
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Organoplatinum Compounds / pharmacology
  • Organoplatinum Compounds / therapeutic use
  • Oxaliplatin


  • Anthracyclines
  • Antineoplastic Agents
  • Cardiac Glycosides
  • Organoplatinum Compounds
  • Oxaliplatin
  • Digoxin