Digoxin, HIF-1, and cancer

In a recent issue of PNAS, Zhang et al. (1) find that digoxin inhibits HIF-1 (a transcription factor highly involved in cancer development) and suggest that this effect might be observed in patients taking this drug. They also report that digoxin blocks tumor growth in mice (1). These data suggest that digoxin has anticancer potential.

The authors observe that digoxin inhibits HIF-1 at 100 nM and discuss that the therapeutic plasma concentrations of digoxin in cardiac patients are ≈10–30 nM (1). Extensive clinical use of digoxin has shown that the therapeutic plasma concentrations of this drug are 1.6 ± 1.0 nM and that higher concentrations induce toxicity because of its narrow therapeutic window (2). These data do not support the idea of HIF-1 being inhibited in patients treated with digoxin.

It has been known for some time that mouse cells are >100 times more resistant than human cells to the effects of digoxin and other cardiac glycosides (3). This means that the anticancer effects induced by digoxin in mice harboring human malignant cells (1) are probably due to interspecies differences in sensitivity and not to selective inhibition of tumor cells. Accordingly, unlike digitoxin, evidence suggests that digoxin does not inhibit the growth of cancer cells selectively (4, 5).

In brief, Zhang et al. (1) demonstrate that cardiac glycosides are a new class of HIF-1 inhibitors. However, it seems unlikely that digoxin inhibits HIF-1 at therapeutic concentrations or that the anticancer effects that they observed in mice are relevant in humans.