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.

• Keywords
• Beclin 1, LC3-II, Na+/K+-ATPase, autosis, bufalin, digoxin, mTOR, ouabain, peruvoside,
• MeSH
• Apoptosis drug effects   MeSH
• Autophagy * drug effects   MeSH
• Biomarkers metabolism   MeSH
• Models, Biological MeSH
• Humans MeSH
• Sodium-Potassium-Exchanging ATPase metabolism   MeSH
• Cardiac Glycosides pharmacology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Biomarkers MeSH
• Sodium-Potassium-Exchanging ATPase MeSH
• Cardiac Glycosides MeSH

Drug repositioning is a successful approach in medicinal research. It significantly simplifies the long-term process of clinical drug evaluation, since the drug being tested has already been approved for another condition. One example of drug repositioning involves cardiac glycosides (CGs), which have, for a long time, been used in heart medicine. Moreover, it has been known for decades that CGs also have great potential in cancer treatment and, thus, many clinical trials now evaluate their anticancer potential. Interestingly, heart failure and cancer are not the only conditions for which CGs could be effectively used. In recent years, the antiviral potential of CGs has been extensively studied, and with the ongoing SARS-CoV-2 pandemic, this interest in CGs has increased even more. Therefore, here, we present CGs as potent and promising antiviral compounds, which can interfere with almost any steps of the viral life cycle, except for the viral attachment to a host cell. In this review article, we summarize the reported data on this hot topic and discuss the mechanisms of antiviral action of CGs, with reference to the particular viral life cycle phase they interfere with.

• Keywords
• COVID-19, Na+/K+-ATPase, cardiac steroids, coronavirus, digitoxin, digoxin, drug repurposing, lanatoside C, ouabain, virus entry,
• MeSH
• Antiviral Agents pharmacology   therapeutic use   MeSH
• COVID-19 MeSH
• Digitoxin MeSH
• Digoxin MeSH
• Virus Internalization drug effects   MeSH
• Humans MeSH
• Neoplasms drug therapy   MeSH
• Ouabain MeSH
• Pandemics MeSH
• Drug Repositioning methods   MeSH
• Virus Replication drug effects   MeSH
• SARS-CoV-2 MeSH
• Sodium-Potassium-Exchanging ATPase MeSH
• Cardiac Glycosides metabolism   therapeutic use   MeSH
• Heart Failure drug therapy   virology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antiviral Agents MeSH
• Digitoxin MeSH
• Digoxin MeSH
• Ouabain MeSH
• Sodium-Potassium-Exchanging ATPase MeSH
• Cardiac Glycosides MeSH

Cardiac glycosides (CGs), toxins well-known for numerous human and cattle poisoning, are natural compounds, the biosynthesis of which occurs in various plants and animals as a self-protective mechanism to prevent grazing and predation. Interestingly, some insect species can take advantage of the CG's toxicity and by absorbing them, they are also protected from predation. The mechanism of action of CG's toxicity is inhibition of Na+/K+-ATPase (the sodium-potassium pump, NKA), which disrupts the ionic homeostasis leading to elevated Ca2+ concentration resulting in cell death. Thus, NKA serves as a molecular target for CGs (although it is not the only one) and even though CGs are toxic for humans and some animals, they can also be used as remedies for various diseases, such as cardiovascular ones, and possibly cancer. Although the anticancer mechanism of CGs has not been fully elucidated, yet, it is thought to be connected with the second role of NKA being a receptor that can induce several cell signaling cascades and even serve as a growth factor and, thus, inhibit cancer cell proliferation at low nontoxic concentrations. These growth inhibitory effects are often observed only in cancer cells, thereby, offering a possibility for CGs to be repositioned for cancer treatment serving not only as chemotherapeutic agents but also as immunogenic cell death triggers. Therefore, here, we report on CG's chemical structures, production optimization, and biological activity with possible use in cancer therapy, as well as, discuss their antiviral potential which was discovered quite recently. Special attention has been devoted to digitoxin, digoxin, and ouabain.

• Keywords
• Na+/K+ ATPase, antiviral potential, cancer treatment, cardenolides, digitoxin, digoxin, drug repositioning, immunogenic cell death, secondary plant metabolites, toxins,
• MeSH
• Molecular Targeted Therapy * MeSH
• Digitoxin pharmacology   toxicity   MeSH
• Digoxin pharmacology   toxicity   MeSH
• Humans MeSH
• Neoplasms drug therapy   MeSH
• Ouabain pharmacology   toxicity   MeSH
• Antineoplastic Agents pharmacology   toxicity   MeSH
• Cattle MeSH
• Sodium-Potassium-Exchanging ATPase antagonists & inhibitors   MeSH
• Cardiac Glycosides biosynthesis   pharmacology   toxicity   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Cattle MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Digitoxin MeSH
• Digoxin MeSH
• Ouabain MeSH
• Antineoplastic Agents MeSH
• Sodium-Potassium-Exchanging ATPase MeSH
• Cardiac Glycosides MeSH