Cardiac Glycosides as Autophagy Modulators

Abstract

Drug repositioning is one of the leading strategies in modern therapeutic research. Instead of searching for completely novel substances and demanding studies of their biological effects, much attention has been paid to the evaluation of commonly used drugs, which could be utilized for more distinct indications than they have been approved for. Since treatment approaches for cancer, one of the most extensively studied diseases, have still been very limited, great effort has been made to find or repurpose novel anticancer therapeutics. One of these are cardiac glycosides, substances commonly used to treat congestive heart failure or various arrhythmias. Recently, the antitumor properties of cardiac glycosides have been discovered and, therefore, these compounds are being considered for anticancer therapy. Their mechanism of antitumor action seems to be rather complex and not fully uncovered yet, however, autophagy has been confirmed to play a key role in this process. In this review article, we report on the up-to-date knowledge of the anticancer activity of cardiac glycosides with special attention paid to autophagy induction, the molecular mechanisms of this process, and the potential employment of this phenomenon in clinical practice.

Dual targets of lethal apoptosis and protective autophagy in liver cancer with periplocymarin elicit a limited therapeutic effect

“…Notably, compelling evidence has shown the anticancer properties of CGs in certain types of cancers and this has highlighted their potential use in cancer therapy. Although the anticancer effects of CGs alone or in combination with other drugs have been verified in both preclinical studies and clinical trials ( 47 ), the MOA of CGs remains unclear. Early studies suggested that the increased susceptibility of tumor cells to these CGs is dependent on the activation of apoptosis ( 48 , 49 ).…”

Proscillaridin A induces mitochondrial damage and autophagy in pancreatic cancer and reduces the stability of SMAD4 in Panc-1 cells

“…Both stimulation and inhibition of autophagy have been proposed as cancer treatment ( 43 ). CGs have been shown to induce autophagy in some cancer types ( 44 - 46 ). Here we show for the first time that Pro A induces autophagy in PC cells, characterized by the changes in the expression of autophagy markers, LC3-I/II, p62 and mTOR pathway ( Figure 7 ).…”

A quantitative high-throughput screen identifies compounds that lower expression of the SCA2-and ALS-associated gene ATXN2

“…Our data suggest that SG modulation is mediated—at least in part—through reduction of ATXN2 and the ATP1A2 pump. In addition, cardiac glycosides including proscillaridin A can also induce autophagy ( 36 ), which might explain their effects on SGs, which are known to be reduced by autophagy ( 37 ).…”