Abstract
Cardiac glycosides stimulate immunogenic cell death that protects against tumor growth.
Major finding: Cardiac glycosides stimulate immunogenic cell death that protects against tumor growth.
Approach: Automated fluorescence microscopy was used to screen for drugs that induce ICD.
Impact: Treatment with digoxin may augment the cytotoxic effect of chemotherapeutics.
Cell death triggered by certain chemotherapeutic drugs, such as anthracyclines, elicits an immune response that is required for efficient cytotoxicity. This immunogenic cell death (ICD) can activate anticancer immune pathways and is characterized by exposure of calreticulin at the cell surface, secretion of ATP from dying cells, and release of the high mobility group box 1 (HMGB1) protein from the nucleus. To identify additional agents that induce ICD, Menger and colleagues devised a fluorescence microscopy–based platform to detect the presence of these biochemical properties of ICD in tumor cells treated with a library of chemical agents. Anthracyclines were among the most effective compounds in promoting the hallmarks of ICD, thus validating this approach. Intriguingly, this screen also identified cardiac glycosides (CG), including digoxin (DIG) and digitoxin, as potent mediators of ICD in several human cancer cell lines. CG-mediated inhibition of the plasma membrane Na+/K+-ATPase and stimulation of Ca2+ influx were necessary for this induction of ICD. In addition, the ability of DIG to stimulate ICD was only observed in immunocompetent mice, supporting an essential role for the immune system in facilitating the antitumor effect of CGs. Treatment with DIG augmented the ability of dying cancer cells to activate an immune response and to protect mice against subsequent tumor growth, suggesting that CGs may improve the clinical response to chemotherapeutic drugs. In support of this idea, a retrospective analysis of a matched patient cohort revealed that patients who received DIG during treatment with nonimmunogenic antitumor therapies showed a significant increase in overall survival. Although additional clinical studies are required, these results suggest that CGs may enhance the efficacy of cytotoxic anticancer drugs.
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