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
Maintenance of Na+ and K+ gradients across the cell plasma membrane is an essential process for mammalian cell survival. An enzyme responsible for this process, sodium-potassium ATPase (NKA), has been currently extensively studied as a potential anticancer target, especially in lung cancer and glioblastoma. To date, many NKA inhibitors, mainly of natural origin from the family of cardiac steroids (CSs), have been reported and extensively studied. Interestingly, upon CS binding to NKA at nontoxic doses, the role of NKA as a receptor is activated and intracellular signaling is triggered, upon which cancer cell death occurs, which lies in the expression of different NKA isoforms than in healthy cells. Two major CSs, digoxin and digitoxin, originally used for the treatment of cardiac arrhythmias, are also being tested for another indication-cancer. Such drug repositioning has a big advantage in smoother approval processes. Besides this, novel CS derivatives with improved performance are being developed and evaluated in combination therapy. This article deals with the NKA structure, mechanism of action, activity modulation, and its most important inhibitors, some of which could serve not only as a powerful tool to combat cancer, but also help to decipher the so-far poorly understood NKA regulation.
- Klíčová slova
- Na+/K+-ATPase activity modulation, anticancer activity, cardiac glycosides, combination therapy, digitoxigenin, digitoxin, digoxin, natural compounds, ouabain, sodium-potassium pump inhibitors,
- MeSH
- digitoxin chemie terapeutické užití MeSH
- digoxin chemie terapeutické užití MeSH
- glioblastom farmakoterapie enzymologie patologie MeSH
- inhibitory enzymů chemie terapeutické užití MeSH
- izoenzymy antagonisté a inhibitory chemie metabolismus MeSH
- klinické zkoušky jako téma MeSH
- konformace proteinů MeSH
- lidé MeSH
- molekulární modely MeSH
- nádory mozku farmakoterapie enzymologie patologie MeSH
- nádory plic farmakoterapie enzymologie patologie MeSH
- ouabain chemie terapeutické užití MeSH
- přehodnocení terapeutických indikací léčivého přípravku MeSH
- protinádorové látky chemie terapeutické užití MeSH
- sodíko-draslíková ATPasa antagonisté a inhibitory chemie metabolismus MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- digitoxin MeSH
- digoxin MeSH
- inhibitory enzymů MeSH
- izoenzymy MeSH
- ouabain MeSH
- protinádorové látky MeSH
- sodíko-draslíková ATPasa MeSH
Pig oocytes matured in vitro were parthenogenetically activated (78%) after treatment with 2 mM nitric oxide-donor (+/-)-S-nitroso-N-acetylpenicillamine (SNAP) for 24 h. Inhibition of soluble guanylyl cyclase with the specific inhibitors 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or 6-anilino-5,8-quinolinequinone (LY83583) suppressed the SNAP-induced activation in a dose-dependent manner (23% of activated oocytes after treatment with 400 microM ODQ; 12% of activated oocytes after treatment with 40 microM LY83583). 8-Bromo-cyclic guanosine monophosphate (8-Br-cGMP), a phosphodiesterase-resistant analogue of cGMP, enhances the effect of suboptimal doses (0.1 or 0.5 mM) of the NO donor SNAP. DT3, a specific inhibitor of cGMP-dependent protein kinase (PKG, PKG), is also able to inhibit the activation of pig oocytes after NO donor treatment. Involvement of the cGMP-dependent signalling pathway is specific for NO-induced oocyte activation, because both the guanylyl cyclase inhibitor ODQ and the PKG inhibitor DT3 are unable to inhibit activation in oocytes treated with the calcium ionophore A23187. These data indicate that the activation of pig oocytes with an NO donor is cGMP-dependent and that PKG plays an important role in this mode of oocyte activation.
- MeSH
- aktivace enzymů účinky léků MeSH
- aminochinoliny metabolismus farmakologie MeSH
- chinoxaliny metabolismus farmakologie MeSH
- digitoxin metabolismus farmakologie MeSH
- fosfodiesterasy metabolismus MeSH
- guanosinmonofosfát cyklický analogy a deriváty metabolismus farmakologie MeSH
- guanylátcyklasa MeSH
- inhibitory proteinkinas metabolismus farmakologie MeSH
- oocyty cytologie účinky léků enzymologie MeSH
- oxadiazoly metabolismus farmakologie MeSH
- oxid dusnatý metabolismus MeSH
- penicilamin analogy a deriváty metabolismus farmakologie MeSH
- permeabilita buněčné membrány účinky léků MeSH
- prasata metabolismus MeSH
- proteinkinasy závislé na cyklickém GMP antagonisté a inhibitory metabolismus MeSH
- receptory cytoplazmatické a nukleární metabolismus MeSH
- rozpustná guanylátcyklasa MeSH
- signální transdukce * účinky léků MeSH
- synthasa oxidu dusnatého metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one MeSH Prohlížeč
- 6-anilino-5,8-quinolinedione MeSH Prohlížeč
- 8-bromocyclic GMP MeSH Prohlížeč
- aminochinoliny MeSH
- chinoxaliny MeSH
- digitoxin MeSH
- fosfodiesterasy MeSH
- guanosinmonofosfát cyklický MeSH
- guanylátcyklasa MeSH
- inhibitory proteinkinas MeSH
- oxadiazoly MeSH
- oxid dusnatý MeSH
- penicilamin MeSH
- proteinkinasy závislé na cyklickém GMP MeSH
- receptory cytoplazmatické a nukleární MeSH
- rozpustná guanylátcyklasa MeSH
- S-nitro-N-acetylpenicillamine MeSH Prohlížeč
- synthasa oxidu dusnatého MeSH
The molecular structure is one of the keypoints that govern both the extent of extracardiac action of cardiac glycosides and their different kinetics. The apolar, fat soluble digitoxin is very well absorbed from the intestine, its onset of action is slow, binds to a high degree to albumin and undergoes enterohepatic recirculation which accounts for a long elimination half time and stability of plasmatic levels. Digitoxin is largely excreted via gastrointestinal tract. The absorption of digoxin is less reliable, onset of action occurs earlier and the binding to albumin is considerably less than that of digitoxin. The drawback, however small, of digoxin lies in a lower stability of plasma levels and prevailing renal excretion. The molecule of strophatin is highly polar, its absorption from the intestine negligible and can be administered only intravenously. The onset of action is prompt, elimination half time short and about half the injected amount is excreted extrarenally.
- MeSH
- digitoxin farmakokinetika MeSH
- digoxin farmakokinetika MeSH
- gastrointestinální nemoci metabolismus MeSH
- lidé MeSH
- nemoci ledvin metabolismus MeSH
- nemoci štítné žlázy metabolismus MeSH
- srdeční glykosidy farmakokinetika MeSH
- strofantiny farmakokinetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- Názvy látek
- digitoxin MeSH
- digoxin MeSH
- srdeční glykosidy MeSH
- strofantiny MeSH
The influence of digoxin, digitoxin and g-strophanthin (ouabain) on the sinus node function (recovery time, sinoatrial conduction time, PP-interval) and on ventricular repolarisation (corrected QT interval and QT during permanent atrial stimulation) was studied in 101 patients (36 with sick sinus syndrome-SSS, 34 with ischaemic heart disease-IHD, and 31 control patients without cardiac disease). Digoxin caused marked prolongation of sinoatrial conduction time (in SSS and in control patients), digitoxin prolonged the PP interval (in IHD and SSS patients); digitoxin and ouabain shortened the QTcorr in SSS patients, ouabain shortened also QT during atrial pacing. The results do not point to specific indication of individual glycosides in sinus node function disturbances. Under certain clinical prerequisites, however, digitoxin can be recommended in ventricular ectopic contractions caused by prolonged or inhomogeneous repolarisation, and also the capacity of ouabain to shorten the repolarisation time deserves attention.
- MeSH
- digitoxin terapeutické užití MeSH
- digoxin terapeutické užití MeSH
- elektrofyziologie MeSH
- elektrokardiografie MeSH
- kardiostimulace umělá MeSH
- kontrakce myokardu účinky léků MeSH
- koronární nemoc farmakoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nodus sinuatrialis účinky léků MeSH
- ouabain terapeutické užití MeSH
- převodní systém srdeční účinky léků MeSH
- syndrom chorého sinu farmakoterapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- Názvy látek
- digitoxin MeSH
- digoxin MeSH
- ouabain MeSH
A significant positive correlation between heart weight and adrenal weight was found in rats with myocardial hypertrophy induced by experimental hyperthyroidism or ligation of the abdominal aorta. The simultaneous administration of digitoxin partly inhibited myocardial hypertrophy after ligation of the abdominal aorta, but not after experimental hyperthyroidism. Digitoxin also inhibited adrenal hypertrophy after ligature of the abdominal aorta but, again, not after experimental hyperthyroidism. The possible existence of an endogenous cardiotropic hormone participating in the development of cardiac hypertrophy from overloading is discussed.
- MeSH
- aorta abdominalis MeSH
- digitoxin farmakologie MeSH
- hormony štítné žlázy farmakologie MeSH
- hypertyreóza komplikace MeSH
- inbrední kmeny potkanů MeSH
- kardiomegalie etiologie patologie MeSH
- krysa rodu Rattus MeSH
- ligace MeSH
- myokard patologie MeSH
- nadledviny patologie MeSH
- velikost orgánu * účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- digitoxin MeSH
- hormony štítné žlázy MeSH
- thyroidin MeSH Prohlížeč
- MeSH
- adrenokortikotropní hormon imunologie MeSH
- antigeny MeSH
- digitoxigenin imunologie farmakologie MeSH
- digoxigenin imunologie farmakologie MeSH
- digoxin analogy a deriváty MeSH
- erytrocyty metabolismus MeSH
- estradiol analogy a deriváty imunologie farmakologie MeSH
- estron analogy a deriváty MeSH
- hormony imunologie MeSH
- hydroxyestrony imunologie farmakologie MeSH
- hydroxytestosterony imunologie farmakologie MeSH
- imunoenzymatické techniky * MeSH
- lidé MeSH
- radionuklidy MeSH
- rubidium metabolismus MeSH
- testosteron analogy a deriváty MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- Názvy látek
- 14-hydroxyestradiol MeSH Prohlížeč
- 14-hydroxyestrone MeSH Prohlížeč
- 14-hydroxytestosterone MeSH Prohlížeč
- adrenokortikotropní hormon MeSH
- antigeny MeSH
- digitoxigenin MeSH
- digoxigenin MeSH
- digoxin MeSH
- estradiol MeSH
- estron MeSH
- hormony MeSH
- hydroxyestrony MeSH
- hydroxytestosterony MeSH
- radionuklidy MeSH
- rubidium MeSH
- testosteron MeSH
- MeSH
- digitoxin aplikace a dávkování metabolismus MeSH
- digoxin aplikace a dávkování metabolismus MeSH
- lidé MeSH
- srdeční glykosidy metabolismus MeSH
- strofantiny aplikace a dávkování metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- Názvy látek
- digitoxin MeSH
- digoxin MeSH
- srdeční glykosidy MeSH
- strofantiny MeSH
- MeSH
- digitoxin farmakologie MeSH
- digoxin farmakologie MeSH
- dospělí MeSH
- lidé MeSH
- matematika MeSH
- srdce účinky léků fyziologie MeSH
- srdeční glykosidy farmakologie MeSH
- strofantiny farmakologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- digitoxin MeSH
- digoxin MeSH
- srdeční glykosidy MeSH
- strofantiny MeSH
