Emergence of Cardiac Glycosides as Potential Drugs: Current and Future Scope for Cancer Therapeutics

Abstract

Cardiac glycosides are natural sterols and constitute a group of secondary metabolites isolated from plants and animals. These cardiotonic agents are well recognized and accepted in the treatment of various cardiac diseases as they can increase the rate of cardiac contractions by acting on the cellular sodium potassium ATPase pump. However, a growing number of recent efforts were focused on exploring the antitumor and antiviral potential of these compounds. Several reports suggest their antitumor properties and hence, today cardiac glycosides (CG) represent the most diversified naturally derived compounds strongly recommended for the treatment of various cancers. Mutated or dysregulated transcription factors have also gained prominence as potential therapeutic targets that can be selectively targeted. Thus, we have explored the recent advances in CGs mediated cancer scope and have considered various signaling pathways, molecular aberration, transcription factors (TFs), and oncogenic genes to highlight potential therapeutic targets in cancer management.

Keywords: cancer therapy; cardiac glycosides; in vitro and in vivo anticancer activities; therapeutic target; transcription factors.

Figure 1

The mode of action of CGs in cancer proceeds through targeting Na⁺/K⁺-ATPase by maintaining the concentration of sodium-potassium gradient across the plasma membrane. CG binds to the Na⁺/K⁺-ATPase pump, thus inhibiting it, resulting in intracellular retention of Na⁺ and increasing the concentration of Ca²⁺. Subsequently, lower expression of Na⁺/K⁺-ATPase causes endoplasmic reticulum stress.

Figure 2

Illustrating the inhibition of transcription factors activated in cancer through cardiac glycosides. The binding of CGs on the Na⁺/K⁺/ATPase (NKA) channel decreases the NKA pump activity and thus down regulates multiple signal transduction cascades especially targeting the TF proteins involved in the cell growth and cell proliferation by providing signals to the transcription machinery. Dysregulated TF and their targeted therapy through CG are represented in the pathway. The scope of targeting nuclear receptors via CG is an upcoming purview to be studied for therapeutic potential.

Figure 3

Molecular mechanisms for the antiproliferative and cytotoxic effects of cardiac glycosides.

Figure 4

Molecular mechanisms associated with cardiac glycoside induced apoptosis.