Figure 3.

Proposed mechanisms of anticancer activity of digoxin. Digoxin is a phytoestrogen which inhibits AR signaling pathway by preventing AR binding to AR-responsive element (ARE), leading to decrease in AR target genes such as PSA in prostate cancer cells. Digoxin is also known to inhibit HIF-1α synthesis, thereby reducing HIF-1α binding to its cognate element, hypoxia-responsive element (HRE), and suppressing the expression of HIF-1α target genes such as VEGF in cancer cells. Binding of cardiac glycosides to Na⁺/K⁺-ATPase is known to activate Src, epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation, which leads to an accumulation of p21/CIP1 and induction of cell cycle arrest in cancer cells.