Cardiac glycosides exert anticancer effects by inducing immunogenic cell death.

Abstract

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.

• Authors: Laurie Menger, Erika Vacchelli, Sandy Adjemian, Isabelle Martins, Yuting Ma, Shensi Shen, Takahiro Yamazaki, Abdul Qader Sukkurwala, Mickaël Michaud, Grégoire Mignot, Frederic Schlemmer, Eric Sulpice, Clara Locher, Xavier Gidrol, François Ghiringhelli, Nazanine Modjtahedi, Lorenzo Galluzzi, Fabrice André, Laurence Zitvogel, Oliver Kepp, Guido Kroemer
• Journal: Science translational medicine (Sci Transl Med) Vol. 4 Issue 143 Pg. 143ra99 (Jul 18 2012) ISSN: 1946-6242 [Electronic] United States
• PMID: 22814852 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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