cardiac glycosides


Summary: Cyclopentanophenanthrenes with a 5- or 6-membered lactone ring attached at the 17-position and SUGARS attached at the 3-position. Plants they come from have long been used in congestive heart failure. They increase the force of cardiac contraction without significantly affecting other parameters, but are very toxic at larger doses. Their mechanism of action usually involves inhibition of the NA(+)-K(+)-EXCHANGING ATPASE and they are often used in cell biological studies for that purpose.

Top Publications

  1. Schoner W, Scheiner Bobis G. Endogenous and exogenous cardiac glycosides and their mechanisms of action. Am J Cardiovasc Drugs. 2007;7:173-89 pubmed
    b>Cardiac glycosides have been used for decades to treat congestive heart failure...
  2. Mijatovic T, Van Quaquebeke E, Delest B, Debeir O, Darro F, Kiss R. Cardiotonic steroids on the road to anti-cancer therapy. Biochim Biophys Acta. 2007;1776:32-57 pubmed
  3. Xie Z, Xie J. The Na/K-ATPase-mediated signal transduction as a target for new drug development. Front Biosci. 2005;10:3100-9 pubmed
  4. Perne A, Muellner M, Steinrueck M, Craig Mueller N, Mayerhofer J, Schwarzinger I, et al. Cardiac glycosides induce cell death in human cells by inhibiting general protein synthesis. PLoS ONE. 2009;4:e8292 pubmed publisher
    b>Cardiac glycosides are Na(+)/K(+)-pump inhibitors widely used to treat heart failure. They are also highly cytotoxic, and studies have suggested specific anti-tumor activity leading to current clinical trials in cancer patients...
  5. Lingrel J. The physiological significance of the cardiotonic steroid/ouabain-binding site of the Na,K-ATPase. Annu Rev Physiol. 2010;72:395-412 pubmed publisher
    ..These studies extend the reach of earlier studies involving the biochemical purification of endogenous regulatory ligands. ..
  6. Shi L, Liao Y, Su M, Lee A, Kuo P, Damu A, et al. Cardiac glycosides from Antiaris toxicaria with potent cardiotonic activity. J Nat Prod. 2010;73:1214-22 pubmed publisher
    ..Bioassay-guided fractionation of the extract led to identification of nine new cardiac glycosides (1-9, named antiarosides A-I), antiarotoxinin A (10), and 18 known compounds...
  7. Egawa K, Kurihara Y, Ito T, Matsumoto M, Nose K. Induction of p16INK4a transcription and of cellular senescence by aclacinomycin-derivatives and cardiac glycosides. Biol Pharm Bull. 2002;25:461-5 pubmed
    ..These results suggest that the reporter system using the p16CDKN2 transcriptional regulatory region is a useful means for screening growth inhibiting substances that are potential anti-tumor agents. ..
  8. Liu J, Periyasamy S, Gunning W, Fedorova O, Bagrov A, Malhotra D, et al. Effects of cardiac glycosides on sodium pump expression and function in LLC-PK1 and MDCK cells. Kidney Int. 2002;62:2118-25 pubmed
    ..However, the circulating concentrations of DLS do not acutely inhibit the sodium pump to a degree consistent with the observed changes in proximal tubule sodium reabsorption...
  9. Tamura M, Harris T, Phillips D, Blair I, Wang Y, Hellerqvist C, et al. Identification of two cardiac glycosides as Na(+)-pump inhibitors in rat urine and diet. J Biol Chem. 1994;269:11972-9 pubmed
    ..These cardiac glycosides exhibited inhibitory potencies comparable to ouabain against ouabain-displacement from Na+,K(+)-ATPase and ..

More Information


  1. Zhang H, Qian D, Tan Y, Lee K, Gao P, Ren Y, et al. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proc Natl Acad Sci U S A. 2008;105:19579-86 pubmed publisher
    ..4 microM. Eleven of these drugs were cardiac glycosides, including digoxin, ouabain, and proscillaridin A, which inhibited HIF-1alpha protein synthesis and ..
  2. Wang Z, Zheng M, Li Z, Li R, Jia L, Xiong X, et al. Cardiac glycosides inhibit p53 synthesis by a mechanism relieved by Src or MAPK inhibition. Cancer Res. 2009;69:6556-64 pubmed publisher
    ..The drugs may be useful in the treatment of human cancers with a gain-of-function p53 mutation. ..
  3. Dai H, Gan Y, Que D, Wu J, Wen Z, Mei W. Two new cytotoxic cardenolides from the latex of Antiaris toxicaria. J Asian Nat Prod Res. 2009;11:832-7 pubmed publisher
    ..Lesch (Moraceae). Their structures were elucidated on the basis of spectral data and chemical evidence. Compounds 1 and 2 showed significant cytotoxicity against K562, SGC-7901, SMMC-7721, and HeLa cell lines in vitro by the MTT method...
  4. Liu T, Brown D, O ROURKE B. Role of mitochondrial dysfunction in cardiac glycoside toxicity. J Mol Cell Cardiol. 2010;49:728-36 pubmed publisher
    b>Cardiac glycosides, which inhibit the plasma membrane Na(+) pump, are one of the four categories of drug recommended for routine use to treat heart failure, yet their therapeutic window is limited by toxic effects...
  5. Wang Y, Qiu Q, Shen J, Li D, Jiang X, Si S, et al. Cardiac glycosides induce autophagy in human non-small cell lung cancer cells through regulation of dual signaling pathways. Int J Biochem Cell Biol. 2012;44:1813-24 pubmed publisher
    ..Although multiple anti-cancer mechanisms of cardiac glycosides as Na(+)/K(+)-ATPase inhibitors are revealed, the role of autophagy and related molecular signaling pathway ..
  6. Xie C, Liu X, Yu S, Cheng C. Cardiac glycosides block cancer growth through HIF-1?- and NF-?B-mediated Plk1. Carcinogenesis. 2013;34:1870-80 pubmed publisher
    b>Cardiac glycosides as inhibitors of the sodium/potassium adenosine triphosphatase (sodium pump) have been reported to block cancer growth by inducing G2/M phase arrest in many cancer cells...
  7. Liu B, Anderson S, Qiu J, Rubin B. Cardiac glycosides correct aberrant splicing of IKBKAP-encoded mRNA in familial dysautonomia derived cells by suppressing expression of SRSF3. FEBS J. 2013;280:3632-46 pubmed publisher
    ..These findings support the clinical evaluation of the impact of digoxin on the FD patient population. ..
  8. Slingerland M, Cerella C, Guchelaar H, Diederich M, Gelderblom H. Cardiac glycosides in cancer therapy: from preclinical investigations towards clinical trials. Invest New Drugs. 2013;31:1087-94 pubmed publisher
    b>Cardiac glycosides have a long history in the treatment of cardiac disease. However, several preclinical studies as well as two phase I studies have shown that cardenolides may also possess anticancer effects...
  9. Katz A, Lifshitz Y, Bab Dinitz E, Kapri Pardes E, Goldshleger R, Tal D, et al. Selectivity of digitalis glycosides for isoforms of human Na,K-ATPase. J Biol Chem. 2010;285:19582-92 pubmed publisher
    ..alpha2 is thought to play a key role in cardiac and smooth muscle contraction and be an important target of cardiac glycosides. An alpha2-selective cardiac glycoside could provide important insights into physiological and ..
  10. Lin J, Denmeade S, Carducci M. HIF-1alpha and calcium signaling as targets for treatment of prostate cancer by cardiac glycosides. Curr Cancer Drug Targets. 2009;9:881-7 pubmed
    ..Digoxin and other cardiac glycosides, known inhibitors of the alpha-subunit of sarcolemmal Na(+)K(+)-ATPase, were recently found to block tumor ..
  11. Babula P, Masarik M, Adam V, Provaznik I, Kizek R. From Na+/K+-ATPase and cardiac glycosides to cytotoxicity and cancer treatment. Anticancer Agents Med Chem. 2013;13:1069-87 pubmed
    The cardiac glycosides are a group of compounds isolated from plants and some animals. They have been used in therapy for heart failure for many years...
  12. Newman R, Yang P, Pawlus A, Block K. Cardiac glycosides as novel cancer therapeutic agents. Mol Interv. 2008;8:36-49 pubmed publisher
    The class of steroid-like compounds designated cardiac glycosides includes well-known drugs such as digoxin, digitoxin, and ouabain...
  13. Newman R, Kondo Y, Yokoyama T, Dixon S, Cartwright C, Chan D, et al. Autophagic cell death of human pancreatic tumor cells mediated by oleandrin, a lipid-soluble cardiac glycoside. Integr Cancer Ther. 2007;6:354-64 pubmed
    Lipid-soluble cardiac glycosides such as bufalin, oleandrin, and digitoxin have been suggested as potent agents that might be useful as anticancer agents. Past research with oleandrin, a principle cardiac glycoside in Nerium oleander L...
  14. Prassas I, Diamandis E. Novel therapeutic applications of cardiac glycosides. Nat Rev Drug Discov. 2008;7:926-35 pubmed publisher
    b>Cardiac glycosides are a diverse family of naturally derived compounds that bind to and inhibit Na+/K+-ATPase...
  15. Wang L, Wible B, Wan X, Ficker E. Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking. J Pharmacol Exp Ther. 2007;320:525-34 pubmed
    ..a surface expression assay to identify novel compounds that interfere with hERG trafficking and found that cardiac glycosides are potent inhibitors of hERG expression at the cell surface...
  16. Schoner W, Scheiner Bobis G. Endogenous cardiac glycosides: hormones using the sodium pump as signal transducer. Semin Nephrol. 2005;25:343-51 pubmed
    ..These effects of endogenous cardiac glycosides are observed at concentrations that do not inhibit the sodium pump...
  17. McConkey D, Lin Y, Nutt L, Ozel H, Newman R. Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells. Cancer Res. 2000;60:3807-12 pubmed
    b>Cardiac glycosides are used clinically to increase contractile force in patients with cardiac disorders...
  18. Juang H, Lin Y, Chang P, Tsui K. Cardiac glycosides decrease prostate specific antigen expression by down-regulation of prostate derived Ets factor. J Urol. 2010;184:2158-64 pubmed publisher
    While cardiac glycosides are the mainstay of congestive heart failure treatment, early studies showed that pharmacological doses of cardiac glycosides inhibited prostate cancer cell line proliferation...
  19. Ye J, Chen S, Maniatis T. Cardiac glycosides are potent inhibitors of interferon-? gene expression. Nat Chem Biol. 2011;7:25-33 pubmed publisher
    ..b>Cardiac glycosides increase the intracellular sodium concentration, which appears to inhibit the ATPase activity of the RNA ..
  20. Komajda M, Follath F, Swedberg K, Cleland J, Aguilar J, Cohen Solal A, et al. The EuroHeart Failure Survey programme--a survey on the quality of care among patients with heart failure in Europe. Part 2: treatment. Eur Heart J. 2003;24:464-74 pubmed
    ..9% followed by ACE inhibitors (61.8%), beta-blockers (36.9%), cardiac glycosides (35.7%), nitrates (32.1%), calcium channel blockers (21.2%) and spironolactone (20.5%). 44...
  21. Ho H, Stevens S, Terentyeva R, Carnes C, Terentyev D, Gyorke S. Arrhythmogenic adverse effects of cardiac glycosides are mediated by redox modification of ryanodine receptors. J Physiol. 2011;589:4697-708 pubmed publisher
    The therapeutic use of cardiac glycosides (CGs), agents commonly used in treating heart failure (HF), is limited by arrhythmic toxicity...
  22. Cerella C, Dicato M, Diederich M. Assembling the puzzle of anti-cancer mechanisms triggered by cardiac glycosides. Mitochondrion. 2013;13:225-34 pubmed publisher
    b>Cardiac glycosides (CGs) are compounds used for the treatment of cardiac failure which also display strong anti-cancer activity inducing impairment of cell proliferation or activation of cell death whether by apoptosis or autophagy...
  23. Sweadner K. Isozymes of the Na+/K+-ATPase. Biochim Biophys Acta. 1989;988:185-220 pubmed
  24. Kirch W. Pressor and vascular effects of cardiac glycosides. Eur J Clin Invest. 2001;31 Suppl 2:5-9 pubmed
    For the past two decades, it has generally been accepted ('Blaustein hypothesis') that cardiac glycosides such as ouabain and digoxin increase the sodium and calcium content of smooth muscle cells, so inducing arterial vasoconstriction ..
  25. Mijatovic T, Dufrasne F, Kiss R. Cardiotonic steroids-mediated targeting of the Na(+)/K(+)-ATPase to combat chemoresistant cancers. Curr Med Chem. 2012;19:627-46 pubmed
    ..Moreover, pharmacological data from in vitro and in vivo experiments, as well as pre-clinical and clinical trials regarding cardenolides to combat cancers associated with dismal prognoses are presented. ..
  26. Lefranc F, Kiss R. The sodium pump alpha1 subunit as a potential target to combat apoptosis-resistant glioblastomas. Neoplasia. 2008;10:198-206 pubmed
    ..Glioblastoma patients who do not respond to chemotherapy and whose tumors over-express NaK alpha1 subunits could benefit from a treatment using ligands with marked binding affinity for the NaK alpha1 subunit. ..
  27. Schoner W. Endogenous cardiac glycosides, a new class of steroid hormones. Eur J Biochem. 2002;269:2440-8 pubmed
    ..compound, which has been isolated from human urine and adrenals, as well various other endogenous cardiac glycosides may counterbalance their actions within a regulatory framework of water and salt metabolism...
  28. Wang J, Portbury S, Thomas M, Barney S, Ricca D, Morris D, et al. Cardiac glycosides provide neuroprotection against ischemic stroke: discovery by a brain slice-based compound screening platform. Proc Natl Acad Sci U S A. 2006;103:10461-10466 pubmed publisher
    ..Neriifolin is structurally related to the digitalis class of cardiac glycosides, and its putative target is the Na(+)/K(+)-ATPase...
  29. Reuter H, Henderson S, Han T, Ross R, Goldhaber J, Philipson K. The Na+-Ca2+ exchanger is essential for the action of cardiac glycosides. Circ Res. 2002;90:305-8 pubmed
    The widely accepted model to explain the positive inotropic effect of cardiac glycosides invokes altered Na+-Ca2+ exchange activity secondary to Na+ pump inhibition...
  30. Simpson C, Mawji I, Anyiwe K, Williams M, Wang X, Venugopal A, et al. Inhibition of the sodium potassium adenosine triphosphatase pump sensitizes cancer cells to anoikis and prevents distant tumor formation. Cancer Res. 2009;69:2739-47 pubmed publisher
    ..This screen identified five members of the family of cardiac glycosides as anoikis sensitizers, including ouabain, peruvoside, digoxin, digitoxin, and strophanthidin...
  31. Middleton D, Rankin S, Esmann M, Watts A. Structural insights into the binding of cardiac glycosides to the digitalis receptor revealed by solid-state NMR. Proc Natl Acad Sci U S A. 2000;97:13602-7 pubmed
  32. Hauck C, Potter T, Bartz M, Wittwer T, Wahlers T, Mehlhorn U, et al. Isoform specificity of cardiac glycosides binding to human Na+,K+-ATPase alpha1beta1, alpha2beta1 and alpha3beta1. Eur J Pharmacol. 2009;622:7-14 pubmed publisher
    b>Cardiac glycosides inhibit the Na(+),K(+)-ATPase and are used for the treatment of symptomatic heart failure and atrial fibrillation...
  33. Guo J, Zheng S, Li Y, Jie W, Hao X, Li T, et al. Toxicarioside A inhibits SGC-7901 proliferation, migration and invasion via NF-?B/bFGF signaling. World J Gastroenterol. 2012;18:1602-9 pubmed publisher
    ..05). These findings suggest that toxicarioside A has an anti-gastric cancer activity and this effect may be achieved partly through down-regulation of NF-?B and bFGF/FGFR1 signaling. ..
  34. Frese S, Frese Schaper M, Andres A, Miescher D, Zumkehr B, Schmid R. Cardiac glycosides initiate Apo2L/TRAIL-induced apoptosis in non-small cell lung cancer cells by up-regulation of death receptors 4 and 5. Cancer Res. 2006;66:5867-74 pubmed
    ..Here, we report that cardiac glycosides, which have been used for the treatment of cardiac failure for many years, sensitize lung cancer cells but ..
  35. Guo L, Qian J, Abrams R, Tang H, Weiser T, Sanders M, et al. The electrophysiological effects of cardiac glycosides in human iPSC-derived cardiomyocytes and in guinea pig isolated hearts. Cell Physiol Biochem. 2011;27:453-62 pubmed publisher
    ..Here we extended the use of FP to evaluate the pharmacological and toxicological properties of cardiac glycosides. FPs were recorded using microelectrode arrays (MEAs) in spontaneously beating hiPSC-CMs...
  36. Kolkhof P, Geerts A, Schafer S, Torzewski J. Cardiac glycosides potently inhibit C-reactive protein synthesis in human hepatocytes. Biochem Biophys Res Commun. 2010;394:233-9 pubmed publisher
    ..We show here that endogenous and plant-derived inhibitors of the Na(+)/K(+)-ATPase, i.e. the cardiac glycosides ouabain and digitoxin, inhibit IL-1beta- and IL-6-induced APP expression in human hepatoma cells and primary ..
  37. Gao J, Wymore R, Wang Y, Gaudette G, Krukenkamp I, Cohen I, et al. Isoform-specific stimulation of cardiac Na/K pumps by nanomolar concentrations of glycosides. J Gen Physiol. 2002;119:297-312 pubmed
    It is well-known that micromolar to millimolar concentrations of cardiac glycosides inhibit Na/K pump activity, however, some early reports suggested nanomolar concentrations of these glycosides stimulate activity...
  38. Schoner W, Scheiner Bobis G. Endogenous and exogenous cardiac glycosides: their roles in hypertension, salt metabolism, and cell growth. Am J Physiol Cell Physiol. 2007;293:C509-36 pubmed
    ..hypothesis, based on the Na(+)/K(+)-ATPase "signalosome," that describes the interaction of cardiac glycosides with the Na(+) pump as machinery activating various signaling pathways via intramembrane and cytosolic ..
  39. Chen R, Chung T, Li F, Yang W, Jinn T, Tzen J. Steroid-like compounds in Chinese medicines promote blood circulation via inhibition of Na+/K+ -ATPase. Acta Pharmacol Sin. 2010;31:696-702 pubmed publisher
    ..promotion of blood circulation may act as active components via the same molecular mechanism triggered by cardiac glycosides, such as ouabain...
  40. Langenhan J, Peters N, Guzei I, Hoffmann F, Thorson J. Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization. Proc Natl Acad Sci U S A. 2005;102:12305-10 pubmed
    ..This report highlights the remarkable advantages of glycorandomization as a powerful tool in glycobiology and drug discovery. ..
  41. Prassas I, Paliouras M, Datti A, Diamandis E. High-throughput screening identifies cardiac glycosides as potent inhibitors of human tissue kallikrein expression: implications for cancer therapies. Clin Cancer Res. 2008;14:5778-84 pubmed publisher
    ..We conclude that cardiac glycosides can dramatically suppress the transcription of KLKs and that these effects may be linked to proto-oncogene (..
  42. Winnicka K, Bielawski K, Bielawska A. Cardiac glycosides in cancer research and cancer therapy. Acta Pol Pharm. 2006;63:109-15 pubmed
    The well known and accepted mode of action of cardiac glycosides is inhibition of the ubiquitous plasma membrane Na+, K+-ATPase that leads to increased intracellular Ca2+ ion concentrations...
  43. Tiwari S, Singh A. Toxic and sub-lethal effects of oleandrin on biochemical parameters of fresh water air breathing murrel, Channa punctatus (Bloch.). Indian J Exp Biol. 2004;42:413-8 pubmed
    ..It supports the view that the oleandrin is safer and may be useful substitute of other piscicides for removing the unwanted freshwater fishes from aquaculture ponds. ..
  44. Srivastava M, Eidelman O, Zhang J, Paweletz C, Caohuy H, Yang Q, et al. Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from cystic fibrosis lung epithelial cells. Proc Natl Acad Sci U S A. 2004;101:7693-8 pubmed
    ..Certain other cardiac glycosides are also active but with much less potency...
  45. Akimova O, Tremblay J, Van Huysse J, Hamet P, Orlov S. Cardiotonic steroid-resistant alpha1-Na+,K+-ATPase rescues renal epithelial cells from the cytotoxic action of ouabain: evidence for a Nai+,Ki+ -independent mechanism. Apoptosis. 2010;15:55-62 pubmed publisher
    ..Our results show that the alpha1R subunit rescues MDCK cells from the cytotoxic action of CTS independently of inhibition of Na(+),K(+)-ATPase-mediated Na(+) and K(+) fluxes and inversion of the [Na(+)](i)/[K(+)](i) ratio. ..
  46. Somogyi J, Kiss G, Pentek E, Csermely P, Ver A. [Diabetes mellitus as a general membrane disease and its consequences]. Orv Hetil. 2001;142:1781-8 pubmed
    ..The acknowledgement of these alterations are very important for the exact planning of the up to date treatment of diabetes. ..
  47. Puschett J. Vascular effects of the bufodienolides. Trans Am Clin Climatol Assoc. 2008;119:103-12; discussion 112 pubmed
    ..We propose that MGB is an important etiologic factor in at least some forms of preeclampsia and that the level of its excretion in the urine may prove to be of diagnostic value. ..
  48. Tamura M, Utsunomiya H, Nakamura M, Landon E. Effect of dietary cardiac glycosides on blood pressure regulation in rats. Can J Physiol Pharmacol. 2000;78:548-56 pubmed
    To investigate the possible physiological significance of dietary cardiac glycosides in blood pressure regulation, the blood pressure of normal Sprague Dawley rats raised on a regular diet, which naturally contains large amounts of Na+-..
  49. Liu Q, Tang J, Hu M, Liu J, Chen H, Gao H, et al. Antiproliferative cardiac glycosides from the latex of Antiaris toxicaria. J Nat Prod. 2013;76:1771-80 pubmed publisher
    ..the latex of Antiaris toxicaria resulted in the isolation of 15 new [antiarosides J-X (1-15)] and 17 known cardiac glycosides. The effects of the cardiac glycosides on apoptosis and the expression of orphan nuclear receptor Nur77 were ..
  50. Abere T, Okoto P, Agoreyo F. Antidiarrhoea and toxicological evaluation of the leaf extract of Dissotis rotundifolia Triana (Melastomataceae). BMC Complement Altern Med. 2010;10:71 pubmed publisher
    ..Phytochemical studies revealed the presence of alkaloids, saponin and cardiac glycosides. The crude ethanol extract and fractions inhibited the growth of E. coli, P. aeruginosa, S. aureus and S...
  51. Mongirdiene A. [Changes in parameters of coagulation system after treatment of chronic heart failure with ?-adrenoblockers, angiotensin-converting enzyme inhibitors, calcium antagonists, diuretics, anticoagulants, antiagregants, cardiac glycosides, and physical exe. Medicina (Kaunas). 2011;47:238-43 pubmed
    ..heart failure with ?-adrenoblockers, angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists, cardiac glycosides, diuretics, anticoagulants, and antiagregants...
  52. Akimova O, Bagrov A, Lopina O, Kamernitsky A, Tremblay J, Hamet P, et al. Cardiotonic steroids differentially affect intracellular Na+ and [Na+]i/[K+]i-independent signaling in C7-MDCK cells. J Biol Chem. 2005;280:832-9 pubmed
    ..Thus, our results show that CTS exhibit distinctly different potency in Na(+),K(+) pump inhibition and triggering of [Na(+)](i)/[K(+)](i)-independent signaling, including cell death. ..
  53. Mijatovic T, Kiss R. Cardiotonic steroids-mediated Na+/K+-ATPase targeting could circumvent various chemoresistance pathways. Planta Med. 2013;79:189-98 pubmed publisher
    ..The aims of this review are to examine the various molecular pathways by which the NaK targeting can be more deleterious to biologically aggressive cancer cells than to normal cells. ..