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.