Involvement of cardiac glycosides targeting Na/K-ATPase in their inhibitory effects on c-Myc expression via its transcription, translation and proteasomal degradation.

This article focuses on the anti-tumor mechanisms of cardiac glycosides (CGs), natural compounds traditionally used to treat heart failure, and their potential repositioning as cancer therapeutics. Using transcriptome profiling of human multiple myeloma AMO1 cells treated with periplocin, a CG, the study found significant down-regulation of the oncogene MYC (c-Myc) at both mRNA and protein levels across various cancer cell lines. The suppression of c-Myc by CGs was linked to the α1-subunit of Na/K-ATPase (α1-NKA), as CG-resistant cells harboring a mutation (D128N) in α1-NKA showed resistance to c-Myc inhibition and reduced sensitivity to CGs. These findings suggest that CGs inhibit c-Myc expression through α1-NKA-mediated pathways involving decreased transcription, reduced global protein synthesis, and enhanced proteasomal degradation, supporting their potential use as anti-cancer agents.