title: 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: INSERM, U848, F-94805 Villejuif, France.
authors: Laurie
authors: L
authors: Menger
authors: Erika
authors: E
authors: Vacchelli
authors: Sandy
authors: S
authors: Adjemian
authors: Isabelle
authors: I
authors: Martins
authors: Yuting
authors: Y
authors: Ma
authors: Shensi
authors: S
authors: Shen
authors: Takahiro
authors: T
authors: Yamazaki
authors: Abdul Qader
authors: AQ
authors: Sukkurwala
authors: Mickaël
authors: M
authors: Michaud
authors: Grégoire
authors: G
authors: Mignot
authors: Frederic
authors: F
authors: Schlemmer
authors: Eric
authors: E
authors: Sulpice
authors: Clara
authors: C
authors: Locher
authors: Xavier
authors: X
authors: Gidrol
authors: François
authors: F
authors: Ghiringhelli
authors: Nazanine
authors: N
authors: Modjtahedi
authors: Lorenzo
authors: L
authors: Galluzzi
authors: Fabrice
authors: F
authors: André
authors: Laurence
authors: L
authors: Zitvogel
authors: Oliver
authors: O
authors: Kepp
authors: Guido
authors: G
authors: Kroemer
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D015374:Biosensing Techniques; D002301:Cardiac Glycosides / Q000494:pharmacology* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004077:Digoxin / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000077150:Oxaliplatin
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D002301:Cardiac Glycosides; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D004077:Digoxin