Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 4, Issue 143, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3003807
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Funding
- Ligue Nationale contre le Cancer (Equipes labellisee)
- Agence Nationale pour la Recherche
- European Commission (Active p53, Apo-Sys, ChemoRes, ApopTrain)
- China Scholarship Council
- Fondation pour la Recherche Medicale
- Institut National du Cancer
- Canceropole Ile-de-France
- Fondation Bettencourt-Schueller
- LabEx Immuno-Oncology
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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.
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