Cardiac Glycosides Activate the Tumor Suppressor and Viral Restriction Factor Promyelocytic Leukemia Protein (PML)

Abstract

Cardiac glycosides (CGs), inhibitors of Na+/K+-ATPase (NKA), used clinically to treat heart failure, have garnered recent attention as potential anti-cancer and anti-viral agents. A high-throughput phenotypic screen designed to identify modulators of promyelocytic leukemia protein (PML) nuclear body (NB) formation revealed the CG gitoxigenin as a potent activator of PML. We demonstrate that multiple structurally distinct CGs activate the formation of PML NBs and induce PML protein SUMOylation in an NKA-dependent fashion. CG effects on PML occur at the post-transcriptional level, mechanistically distinct from previously described PML activators and are mediated through signaling events downstream of NKA. Curiously, genomic deletion of PML in human cancer cells failed to abrogate the cytotoxic effects of CGs and other apoptotic stimuli such as ceramide and arsenic trioxide that were previously shown to function through PML in mice. These findings suggest that alternative pathways can compensate for PML loss to mediate apoptosis in response to CGs and other apoptotic stimuli.

Antitumour effect of odoroside A and its derivative on human leukaemia cells through the ROS/JNK pathway

“…They exert pharmacological actions by blocking the membrane-bound sodium-potassium-activated ATPase (Na + /K + -ATPase), leading to a rise in intracellular calcium. 7,8 Moreover, cardiac glycosides have also been reported with potential antitumour effects, where digitoxin displays strong effects of growth inhibition on breast and brain cancers. 9,10 Lots of active natural ingredients exacted from a folk medicine, Nerium oleander Linn.…”

“…Cardiac glycosides, such as digoxin and digitoxin, are commonly used in clinical practice of cardiology for the treatment of cardiac congestion and cardiac arrhythmias, due to their effects of increasing the force of muscle contraction while reducing the heart rate. They exert pharmacological actions by blocking the membrane‐bound sodium‐potassium‐activated ATPase (Na + /K + ‐ATPase), leading to a rise in intracellular calcium 7,8 . Moreover, cardiac glycosides have also been reported with potential antitumour effects, where digitoxin displays strong effects of growth inhibition on breast and brain cancers 9,10 …”

New Cardenolides from Biotransformation of Gitoxigenin by the Endophytic Fungus Alternaria eureka 1E1BL1: Characterization and Cytotoxic Activities

“…Despite the fact that high concentrations of gitoxigenin have poisonous effects, it has been known that certain doses have therapeutic effects on congestive heart failure and atrial arrhythmia. Thus, gitoxigenin is a promising natural product present in a variety of plants [18,19].…”

Redox-responsive PEGylated self-assembled prodrug-nanoparticles formed by single disulfide bond bridge periplocymarin-vitamin E conjugate for liver cancer chemotherapy

“…Chemically, cardiac glycosides are divided into two types namely cardenolides and bufadienolides. Recently, cardiac glycosides have been shown to exhibit great potential in inhibiting the growth of malignant tumor cells and inducing cancer cells apoptosis, and have attracted much attention in the prevention and treatment of cancer (Milutinovic et al., 2016 ; Diederich et al., 2017 ). Digoxinum, Strophanthin G, and UNBS1450 (semi-synthetic drug) have been subjected to clinical studies, but their therapeutic effect in cancer or tumor treatment are not satisfactory.…”