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. 2012 Dec 1;1(9):1640-1642.
doi: 10.4161/onci.21684.

Anticancer activity of cardiac glycosides: At the frontier between cell-autonomous and immunological effects

Oliver Kepp  1 , Laurie Menger, Erika Vacchelli, Sandy Adjemian, Isabelle Martins, Yuting Ma, Abdul Qader Sukkurwala, Mickaël Michaud, Lorenzo Galluzzi, Laurence Zitvogel, Guido Kroemer
Affiliations

Anticancer activity of cardiac glycosides: At the frontier between cell-autonomous and immunological effects

Oliver Kepp et al. Oncoimmunology. .

Abstract

Retrospective clinical data indicate that cardiac glycosides (CGs), notably digoxin, prolong the survival of carcinoma patients treated with conventional chemotherapy. CGs are known to influence the immune response at multiple levels. In addition, recent results suggest that CGs trigger the immunogenic demise of cancer cells, an effect that most likely contributes to their clinical anticancer activity.

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Figures

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Figure 1. Proposed mode of action of cardiac glycosides. Cardiac glycosides (CGs) bind to (and hence inhibit) the plasma membrane Na+/K+ ATPase, resulting in the accumulation of intracellular Na+ ions. As the Na+ gradient [Δ(Na+)] normally drives Ca2+ extrusion via the Na+/Ca2+ exchanger, CGs increase the intracellular concentration of Ca2+ [(Ca2+)intra], which is readily taken up by the endoplasmic reticulum and by mitochondria (A). In cardiomyocytes, this allows for an increased release of Ca2+ from the endoplasmic reticulum (via inositol 1,4,5-trisphosphate-gated channels) in response to contraction stimuli, de facto improving the cardiac performance. Conversely, cancer cells express particular Na+/K+ ATPase subunits and hence respond to CGs with an endoplasmic reticulum stress that eventually is lethal. Thus, CGs can induce immunogenic cell death (ICD), featuring the exposure of calreticulin (CRT) at the cell surface, the secretion of ATP as well as the release of the nuclear protein HMGB1 into the extracellular space (B). Pi, inorganic phosphate.
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