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.

• Klíčová slova
• Beclin 1, LC3-II, Na+/K+-ATPase, autosis, bufalin, digoxin, mTOR, ouabain, peruvoside,
• MeSH
• apoptóza účinky léků   MeSH
• autofagie * účinky léků   MeSH
• biologické markery metabolismus   MeSH
• biologické modely MeSH
• lidé MeSH
• sodíko-draslíková ATPasa metabolismus   MeSH
• srdeční glykosidy farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• biologické markery MeSH
• sodíko-draslíková ATPasa MeSH
• srdeční glykosidy 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.

• Klíčová slova
• COVID-19, Na+/K+-ATPase, cardiac steroids, coronavirus, digitoxin, digoxin, drug repurposing, lanatoside C, ouabain, virus entry,
• MeSH
• antivirové látky farmakologie   terapeutické užití   MeSH
• COVID-19 MeSH
• digitoxin MeSH
• digoxin MeSH
• internalizace viru účinky léků   MeSH
• lidé MeSH
• nádory farmakoterapie   MeSH
• ouabain MeSH
• pandemie MeSH
• přehodnocení terapeutických indikací léčivého přípravku metody   MeSH
• replikace viru účinky léků   MeSH
• SARS-CoV-2 MeSH
• sodíko-draslíková ATPasa MeSH
• srdeční glykosidy metabolismus   terapeutické užití   MeSH
• srdeční selhání farmakoterapie   virologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antivirové látky MeSH
• digitoxin MeSH
• digoxin MeSH
• ouabain MeSH
• sodíko-draslíková ATPasa MeSH
• srdeční glykosidy 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.

• Klíčová slova
• Na+/K+ ATPase, antiviral potential, cancer treatment, cardenolides, digitoxin, digoxin, drug repositioning, immunogenic cell death, secondary plant metabolites, toxins,
• MeSH
• cílená molekulární terapie * MeSH
• digitoxin farmakologie   toxicita   MeSH
• digoxin farmakologie   toxicita   MeSH
• lidé MeSH
• nádory farmakoterapie   MeSH
• ouabain farmakologie   toxicita   MeSH
• protinádorové látky farmakologie   toxicita   MeSH
• skot MeSH
• sodíko-draslíková ATPasa antagonisté a inhibitory   MeSH
• srdeční glykosidy biosyntéza   farmakologie   toxicita   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• digitoxin MeSH
• digoxin MeSH
• ouabain MeSH
• protinádorové látky MeSH
• sodíko-draslíková ATPasa MeSH
• srdeční glykosidy MeSH

Cardiac glycosides (CGs) are natural steroid compounds occurring both in plants and animals. They are known for long as cardiotonic agents commonly used for various cardiac diseases due to inhibition of Na+/K+-ATPase (NKA) pumping activity and modulating heart muscle contractility. However, recent studies show that the portfolio of diseases potentially treatable with CGs is much broader. Currently, CGs are mostly studied as anticancer agents. Their antiproliferative properties are based on the induction of multiple signaling pathways in an NKA signalosome complex. In addition, they are strongly connected to immunogenic cell death, a complex mechanism of induction of anticancer immune response. Moreover, CGs exert various immunomodulatory effects, the foremost of which are connected with suppressing the activity of T-helper cells or modulating transcription of many immune response genes by inhibiting nuclear factor kappa B. The resulting modulations of cytokine and chemokine levels and changes in immune cell ratios could be potentially useful in treating sundry autoimmune and inflammatory diseases. This review aims to summarize current knowledge in the field of immunomodulatory properties of CGs and emphasize the large area of potential clinical use of these compounds.

• Klíčová slova
• NKA signalosome, Th17, anticancer compounds, calreticulin, cardiac steroids, immunogenic cell death, inflammation, interleukin 17, retinoic acid receptor-related orphan receptor γ thymus, sodium-potassium ATPase,
• MeSH
• cytokiny metabolismus   MeSH
• imunologické faktory farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nádory farmakoterapie   imunologie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• sodíko-draslíková ATPasa metabolismus   MeSH
• srdeční glykosidy farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• cytokiny MeSH
• imunologické faktory MeSH
• protinádorové látky MeSH
• sodíko-draslíková ATPasa MeSH
• srdeční glykosidy MeSH