Cardiac Glycosides Exert Anticancer Effects by Inducing Immunogenic Cell Death

Cardiac glycosides kill cancer cells in a way that stimulates the immune response. A Cancer Double Feature—3807 A traditional chemotherapeutic drug performs a one-act play: It enters and kills a dividing cancer cell and then takes its bow. However, some chemotherapeutics have a wider range—they not only kill individual cancer cells but also do so in such a way that the dead cells function as a vaccine that primes the immune system to attack other cancer cells. Menger et al. now identify cardiac glycosides as potent inducers of this so-called immunogenic cell death. Using fluorescence microscopy to detect the hallmarks of immunogenic cell death, the authors identified cardiac glycosides, such as the heart drug digoxin, as immunogenic cell death inducers. They then verified that these drugs had anticancer effects in mice with intact immune systems but not in mice that lacked functional immunity. Cancer cells that died from digoxin exposure then effectively functioned as a vaccine—stimulating the immune system so that growth of future cancers is prevented. Indeed, human cancer patients on chemotherapy who happened to be taking the cardiac glycoside digoxin to treat other medical conditions had improved overall survival compared with patients who were not taking these drugs. Although efficacy in cancer patients remains to be formally tested, cardiac glycosides may augment chemotherapeutic response—forcing cancer to bow out. 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.