Cardiac Glycosides as Novel Cancer Therapeutic Agents

  Figure 2.
Figure 2.

The Na+,K+-ATPase signalosome complex. The binding of selected cardiac glycosides (CGs)––such as oleandrin, bufalin, and digitoxin––to Na+,K+-ATPase results in complex but well-documented changes in cell signaling events. The “signalosome” complex includes the enzyme, Na+,K+-ATPase as well as Src, phosphoinositide-3 kinase (PI3K), and phospholipase C each of which, in turn, sets into action complex signaling events that can result in tumor cell death through either apoptosis or autophagy-related mechanisms. Administration of CGs can (A) increase the (cell surface) expression of death receptors (DR4, DR5) and activate caspase activity; (B) result in increased intracellular calcium concentrations, which, in turn, (C) decreases the expression of transcription factors such as Activator Protein-1 (AP-1). CG treatment can also (D) inhibit activation (i.e., block the phosphorylation) of Akt, which normally blocks apoptosis; (E) inhibit activation of the transcription factor Nuclear Factor-kappaB (NF-κ B); (F) activate the Ras pathway, leading to increase activity of Raf–MAPK pathway; (G) activate Src; (H) inhibit tumor necrosis factor (TNF)-mediated activation of NF-κ B by inhibiting the binding of tumor necrosis factor receptor 1–associated death domain protein (TRADD) to the cellular membrane; (I) inhibit extracellular transport of tumor growth factors, such as fibroblast growth factor-2 (FGF-2); (J) alter membrane fluidity which, in turn, may inhibit Fas-related signaling; (K) lead to the production of reactive oxygen species (ROS) with subsequent injury to mitochondria; (L) produce a decrease in mitochondria membrane potential and a decrease in quantity of anti-apoptotic proteins Bcl-XL and Bcl-2 and topoisomerases I and II; and (M) cause mitochondrial condensation and loss of function, that, in turn, can lead to autophagic processes and cell death (N). Adapted from (30).

This Article

  1. MI February 2008 vol. 8 no. 1 36-49