Cardiac glycosides such as digitoxin and digoxin are Na,K-ATPase inhibitors, and they have been used clinically for treatment of heart failure. Interestingly, lower recurrence of cancer and improvement of their survival are suggested in cancer patients who have been taking cardiac glycosides. In the cancer cells, it has been reported that sub-micromolar cardiac glycosides showed anti-cancer effects without affecting Na,,K-ATPase activity. We found recently that the receptor-type Na,K-ATPase, which has no pumping activity, is specifically associated with LRRC8A, an component of volume-regulated anion channel (VRAC), in the membrane microdomains of plasma membrane of cancer cells, and that functional relation between them is involved in the inhibitory mechanism of submicromolar cardiac glycosides for cancer cell growth. In this mechanism, binding of cardiac glycosides to the receptor-type Na,K-ATPase stimulates the production of reactive oxygen species by NADPH oxidase, and they activate VRAC within membrane microdomains, thus eliciting anti-proliferative effects. Of note, digoxin and digitoxin showed anti-proliferative effects in cancer cells at their therapeutic concentration ranges. These effects were not observed in non-cancer cells.

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