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Novel therapeutic applications of cardiac glycosides

Key Points

  • Cardiac glycosides constitute a diverse family of naturally derived compounds widely known for their ability to bind to and inhibit the sodium pump.

  • Members of this family have been used in the clinic for many years for the treatment of heart failure and atrial arrhythmia.

  • Recent findings report additional signalling modes of action of the sodium pump and implicate cardiac glycosides in the regulation of several important cellular processes, including gene-expression profiling, apoptosis, proliferation and cell–cell interactions.

  • Cancer cells are more vulnerable to the effects of these compounds compared with normal cells. The increased susceptibility of cancer cells to these compounds supports their potential use as novel antineoplastic agents.

  • Early epidemiological studies in patients with heart failure under cardiac glycoside treatment revealed the potential use of these drugs as novel antineoplastic agents.

  • Accumulating studies from the past decade verify the anticancer effects of these drugs both in vitro and in vivo. The first generation of cardiac-glycoside-based anticancer drugs is currently in clinical trials (for example, Anvirzel and UNBS1450).

  • Novel insights into the mode of action of these drugs reveal potential therapeutic uses of these drugs for the treatment of several diseases, including cystic fibrosis, ischaemic stroke and neurodegenerative diseases.

Abstract

Cardiac glycosides are a diverse family of naturally derived compounds that bind to and inhibit Na+/K+-ATPase. Members of this family have been in clinical use for many years for the treatment of heart failure and atrial arrhythmia, and the mechanism of their positive inotropic effect is well characterized. Exciting recent findings have suggested additional signalling modes of action of Na+/K+-ATPase, implicating cardiac glycosides in the regulation of several important cellular processes and highlighting potential new therapeutic roles for these compounds in various diseases. Perhaps most notably, the increased susceptibility of cancer cells to these compounds supports their potential use as cancer therapies, and the first generation of glycoside-based anticancer drugs are currently in clinical trials.

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Figure 1: General structural characteristics of cardiac glycosides.
Figure 2: Na+/K+-ATPase as a versatile signal transducer.

References

  1. Schatzmann, H. J. & Rass, B. Inhibition of the active Na-K-transport and Na-K-activated membrane ATP-ase of erythrocyte stroma by ouabain. Helv. Physiol. Pharmacol. Acta 65, C47–C49 (1965) (in German).

    CAS  PubMed  Google Scholar 

  2. Rahimtoola, S. H. & Tak, T. The use of digitalis in heart failure. Curr. Probl. Cardiol. 21, 781–853 (1996).

    CAS  PubMed  Google Scholar 

  3. Xie, Z. & Askari, A. Na+/K+-ATPase as a signal transducer. Eur. J. Biochem. 269, 2434–2439 (2002).

    CAS  PubMed  Google Scholar 

  4. Aizman, O. & Aperia, A. Na, K-ATPase as a signal transducer. Ann. NY Acad. Sci. 986, 489–496 (2003).

    CAS  PubMed  Google Scholar 

  5. Aperia, A. New roles for an old enzyme: Na, K-ATPase emerges as an interesting drug target. J. Intern. Med. 261, 44–52 (2007).

    CAS  PubMed  Google Scholar 

  6. Kometiani, P., Liu, L. & Askari, A. Digitalis-induced signaling by Na+/K+-ATPase in human breast cancer cells. Mol. Pharmacol. 67, 929–936 (2005).

    CAS  PubMed  Google Scholar 

  7. Schoner, W. & Scheiner-Bobis, G. Endogenous and exogenous cardiac glycosides and their mechanisms of action. Am. J. Cardiovasc. Drugs 7, 173–189 (2007).

    CAS  PubMed  Google Scholar 

  8. Schoner, W. & Scheiner-Bobis, G. Endogenous and exogenous cardiac glycosides: their roles in hypertension, salt metabolism, and cell growth. Am. J. Physiol. Cell Physiol. 293, C509–C536 (2007).

    CAS  PubMed  Google Scholar 

  9. Schoner, W. Endogenous cardiac glycosides, a new class of steroid hormones. Eur. J. Biochem. 269, 2440–2448 (2002).

    CAS  PubMed  Google Scholar 

  10. Mijatovic, T. et al. Cardiotonic steroids on the road to anti-cancer therapy. Biochim. Biophys. Acta 1776, 32–57 (2007). An excellent up-to-date review on the anticancer effects of cardiac glycosides.

    CAS  PubMed  Google Scholar 

  11. Winnicka, K., Bielawski, K. & Bielawska, A. Cardiac glycosides in cancer research and cancer therapy. Acta Pol. Pharm. 63, 109–115 (2006).

    CAS  PubMed  Google Scholar 

  12. Lopez-Lazaro, M. Digitoxin as an anticancer agent with selectivity for cancer cells: possible mechanisms involved. Expert. Opin. Ther. Targets. 11, 1043–1053 (2007).

    CAS  PubMed  Google Scholar 

  13. Mekhail, T. et al. Phase 1 trial of Anvirzel in patients with refractory solid tumors. Invest. New Drugs 24, 423–427 (2006).

    CAS  PubMed  Google Scholar 

  14. Newman, R. A., Yang, P., Pawlus, A. D. & Block, K. I. Cardiac glycosides as novel cancer therapeutic agents. Mol. Interv. 8, 36–49 (2008).

    CAS  PubMed  Google Scholar 

  15. Mijatovic, T. et al. Cardenolide-induced lysosomal membrane permeabilization demonstrates therapeutic benefits in experimental human non-small cell lung cancers. Neoplasia 8, 402–412 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Schonfeld, W. et al. The lead structure in cardiac glycosides is 5β,14β-androstane-3β14-diol. Naunyn Schmiedebergs Arch. Pharmacol. 329, 414–426 (1985).

    CAS  PubMed  Google Scholar 

  17. Melero, C. P., Medardea, M. & Feliciano, A. S. A short review on cardiotonic steroids and their aminoguanidine analogues. Molecules 5, 51–81 (2000).

    CAS  Google Scholar 

  18. Langenhan, J. M., Peters, N. R., Guzei, I. A., Hoffmann, F. M. & Thorson, J. S. Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization. Proc. Natl Acad. Sci. USA 102, 12305–12310 (2005). The first report on neoglycorandomization as a novel high-throughput method to study the relationship between attached sugars and the biological activity of cardiac glycosides.

    CAS  PubMed  Google Scholar 

  19. Steyn, P. S. & van Heerden, F. R. Bufadienolides of plant and animal origin. Nat. Prod. Rep. 15, 397–413 (1998).

    CAS  PubMed  Google Scholar 

  20. Mathews, W. R. et al. Mass spectral characterization of an endogenous digitalislike factor from human plasma. Hypertension 17, 930–935 (1991).

    CAS  PubMed  Google Scholar 

  21. Goto, A., Yamada, K., Ishii, M. & Sugimoto, T. Digitalis-like activity in human plasma: relation to blood pressure and sodium balance. Am. J. Med. 89, 420–426 (1990).

    CAS  PubMed  Google Scholar 

  22. Weidemann, H. Na/K-ATPase, endogenous digitalis like compounds and cancer development — a hypothesis. Front. Biosci. 10, 2165–2176 (2005).

    CAS  PubMed  Google Scholar 

  23. Hamlyn, J. M. et al. Identification and characterization of a ouabain-like compound from human plasma. Proc. Natl. Acad. Sci. USA 88, 6259–6263 (1991).

    CAS  PubMed  Google Scholar 

  24. Schneider, R. et al. Bovine adrenals contain, in addition to ouabain, a second inhibitor of the sodium pump. J. Biol. Chem. 273, 784–792 (1998).

    CAS  PubMed  Google Scholar 

  25. Kawamura, A. et al. On the structure of endogenous ouabain. Proc. Natl Acad. Sci. USA 96, 6654–6659 (1999).

    CAS  PubMed  Google Scholar 

  26. Komiyama, Y. et al. Identification of endogenous ouabain in culture supernatant of PC12 cells. J. Hypertens. 19, 229–236 (2001).

    CAS  PubMed  Google Scholar 

  27. Lichtstein, D. et al. Identification of digitalis-like compounds in human cataractous lenses. Eur. J. Biochem. 216, 261–268 (1993).

    CAS  PubMed  Google Scholar 

  28. Bagrov, A. Y. et al. Characterization of a urinary bufodienolide Na+, K+-ATPase inhibitor in patients after acute myocardial infarction. Hypertension 31, 1097–1103 (1998).

    CAS  PubMed  Google Scholar 

  29. Schneider, R. et al. Proscillaridin A immunoreactivity: its purification, transport in blood by a specific binding protein and its correlation with blood pressure. Clin. Exp. Hypertens. 20, 593–599 (1998).

    CAS  PubMed  Google Scholar 

  30. Qazzaz, H. M., Cao, Z., Bolanowski, D. D., Clark, B. J. & Valdes, R. Jr. De novo biosynthesis and radiolabeling of mammalian digitalis-like factors. Clin. Chem. 50, 612–620 (2004).

    CAS  PubMed  Google Scholar 

  31. Kaplan, J. H. Biochemistry of Na, K-ATPase. Annu. Rev. Biochem. 71, 511–535 (2002).

    CAS  PubMed  Google Scholar 

  32. Smith, T. W. The fundamental mechanism of inotropic action of digitalis. Therapie 44, 431–435 (1989).

    CAS  PubMed  Google Scholar 

  33. Jorgensen, P. L., Hakansson, K. O. & Karlish, S. J. Structure and mechanism of Na, K-ATPase: functional sites and their interactions. Annu. Rev. Physiol. 65, 817–849 (2003).

    CAS  PubMed  Google Scholar 

  34. Morth, J. P. et al. Crystal structure of the sodium–potassium pump. Nature 450, 1043–1049 (2007). The X-ray crystal structure of Na+/K+-ATPase resolved at 3.5 Å.

    CAS  PubMed  Google Scholar 

  35. Qiu, L. Y. et al. Reconstruction of the complete ouabain-binding pocket of Na, K-ATPase in gastric H, K-ATPase by substitution of only seven amino acids. J. Biol. Chem. 280, 32349–32355 (2005).

    CAS  PubMed  Google Scholar 

  36. Qiu, L. Y. et al. Conversion of the low affinity ouabain-binding site of non-gastric H, K-ATPase into a high affinity binding site by substitution of only five amino acids. J. Biol. Chem. 281, 13533–13539 (2006).

    CAS  PubMed  Google Scholar 

  37. Dostanic-Larson, I. et al. Physiological role of the α1- and α2-isoforms of the Na+-K+-ATPase and biological significance of their cardiac glycoside binding site. Am. J. Physiol. Regul. Integr. Comp. Physiol. 290, R524–R528 (2006).

    CAS  PubMed  Google Scholar 

  38. Delprat, B., Bibert, S. & Geering, K. FXYD proteins: novel regulators of Na, K-ATPase. Med. Sci. (Paris) 22, 633–638 (2006) (in French).

    Google Scholar 

  39. Geering, K. Function of FXYD proteins, regulators of Na, K-ATPase. J. Bioenerg. Biomembr. 37, 387–392 (2005).

    CAS  PubMed  Google Scholar 

  40. Nguyen, A. N., Wallace, D. P. & Blanco, G. Ouabain binds with high affinity to the Na, K-ATPase in human polycystic kidney cells and induces extracellular signal-regulated kinase activation and cell proliferation. J. Am. Soc. Nephrol. 18, 46–57 (2007).

    CAS  PubMed  Google Scholar 

  41. Blanco, G. Na, K-ATPase subunit heterogeneity as a mechanism for tissue-specific ion regulation. Semin. Nephrol. 25, 292–303 (2005).

    CAS  PubMed  Google Scholar 

  42. Sverdlov, E. D. et al. Na+, K+-ATPase: tissue-specific expression of genes coding for α-subunit in diverse human tissues. FEBS Lett. 239, 65–68 (1988).

    CAS  PubMed  Google Scholar 

  43. Geering, K. et al. FXYD proteins: new tissue- and isoform-specific regulators of Na, K-ATPase. Ann. NY Acad. Sci. 986, 388–394 (2003).

    CAS  PubMed  Google Scholar 

  44. Mobasheri, A. et al. Na+, K+-ATPase isozyme diversity; comparative biochemistry and physiological implications of novel functional interactions. Biosci. Rep. 20, 51–91 (2000).

    CAS  PubMed  Google Scholar 

  45. Haas, M., Wang, H., Tian, J. & Xie, Z. Src-mediated inter-receptor cross-talk between the Na+/K+-ATPase and the epidermal growth factor receptor relays the signal from ouabain to mitogen-activated protein kinases. J. Biol. Chem. 277, 18694–18702 (2002).

    CAS  PubMed  Google Scholar 

  46. Haas, M., Askari, A. & Xie, Z. Involvement of Src and epidermal growth factor receptor in the signal-transducing function of Na+/K+-ATPase. J. Biol. Chem. 275, 27832–27837 (2000).

    CAS  PubMed  Google Scholar 

  47. Yuan, Z. et al. Na/K-ATPase tethers phospholipase C and IP3 receptor into a calcium-regulatory complex. Mol. Biol. Cell 16, 4034–4045 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Segall, L., Javaid, Z. Z., Carl, S. L., Lane, L. K. & Blostein, R. Structural basis for α1 versus α2 isoform-distinct behavior of the Na, K-ATPase. J. Biol. Chem. 278, 9027–9034 (2003).

    CAS  PubMed  Google Scholar 

  49. Liu, L., Abramowitz, J., Askari, A. & Allen, J. C. Role of caveolae in ouabain-induced proliferation of cultured vascular smooth muscle cells of the synthetic phenotype. Am. J. Physiol. Heart Circ. Physiol. 287, H2173–H2182 (2004).

    CAS  PubMed  Google Scholar 

  50. Barwe, S. P. et al. Novel role for Na, K-ATPase in phosphatidylinositol 3-kinase signaling and suppression of cell motility. Mol. Biol. Cell 16, 1082–1094 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Wang, X. Q. et al. Apoptotic insults impair Na+, K+-ATPase activity as a mechanism of neuronal death mediated by concurrent ATP deficiency and oxidant stress. J. Cell Sci. 116, 2099–2110 (2003).

    CAS  PubMed  Google Scholar 

  52. Aizman, O., Uhlen, P., Lal, M., Brismar, H. & Aperia, A. Ouabain, a steroid hormone that signals with slow calcium oscillations. Proc. Natl Acad. Sci. USA 98, 13420–13424 (2001).

    CAS  PubMed  Google Scholar 

  53. Saunders, R. & Scheiner-Bobis, G. Ouabain stimulates endothelin release and expression in human endothelial cells without inhibiting the sodium pump. Eur. J. Biochem. 271, 1054–1062 (2004).

    CAS  PubMed  Google Scholar 

  54. Zhang, S. et al. Distinct role of the N-terminal tail of the Na, K-ATPase catalytic subunit as a signal transducer. J. Biol. Chem. 281, 21954–21962 (2006).

    CAS  PubMed  Google Scholar 

  55. Liang, M., Cai, T., Tian, J., Qu, W. & Xie, Z. J. Functional characterization of Src-interacting Na/K-ATPase using RNA interference assay. J. Biol. Chem. 281, 19709–19719 (2006).

    CAS  PubMed  Google Scholar 

  56. Dolmetsch, R. E., Xu, K. & Lewis, R. S. Calcium oscillations increase the efficiency and specificity of gene expression. Nature 392, 933–936 (1998).

    CAS  Google Scholar 

  57. Li, J., Zelenin, S., Aperia, A. & Aizman, O. Low doses of ouabain protect from serum deprivation-triggered apoptosis and stimulate kidney cell proliferation via activation of NF-κB. J. Am. Soc. Nephrol. 17, 1848–1857 (2006).

    CAS  PubMed  Google Scholar 

  58. Xie, Z. & Cai, T. Na+-K+-ATPase-mediated signal transduction: from protein interaction to cellular function. Mol. Interv. 3, 157–168 (2003). An excellent review of the signalling properties of the sodium pump, which emphasizes the structural and functional characteristics of the signalosome domain.

    CAS  PubMed  Google Scholar 

  59. Tian, J., Liu, J., Garlid, K. D., Shapiro, J. I. & Xie, Z. Involvement of mitogen-activated protein kinases and reactive oxygen species in the inotropic action of ouabain on cardiac myocytes. A potential role for mitochondrial KATP channels. Mol. Cell Biochem. 242, 181–187 (2003).

    CAS  PubMed  Google Scholar 

  60. Yudowski, G. A. et al. Phosphoinositide-3 kinase binds to a proline-rich motif in the Na+, K+-ATPase alpha subunit and regulates its trafficking. Proc. Natl Acad. Sci. USA 97, 6556–6561 (2000).

    CAS  PubMed  Google Scholar 

  61. Eva, A., Kirch, U. & Scheiner-Bobis, G. Signaling pathways involving the sodium pump stimulate NO production in endothelial cells. Biochim. Biophys. Acta 1758, 1809–1814 (2006).

    CAS  PubMed  Google Scholar 

  62. Xie, Z. et al. Intracellular reactive oxygen species mediate the linkage of Na+/K+-ATPase to hypertrophy and its marker genes in cardiac myocytes. J. Biol. Chem. 274, 19323–19328 (1999).

    CAS  PubMed  Google Scholar 

  63. Baudouin-Legros, M., Brouillard, F., Tondelier, D., Hinzpeter, A. & Edelman, A. Effect of ouabain on CFTR gene expression in human Calu-3 cells. Am. J. Physiol. Cell Physiol. 284, C620–C626 (2003).

    CAS  PubMed  Google Scholar 

  64. Contreras, R. G., Shoshani, L., Flores-Maldonado, C., Lazaro, A. & Cereijido, M. Relationship between Na+, K+-ATPase and cell attachment. J. Cell Sci. 112, 4223–4232 (1999).

    CAS  PubMed  Google Scholar 

  65. Rajasekaran, S. A. et al. Na, K-ATPase activity is required for formation of tight junctions, desmosomes, and induction of polarity in epithelial cells. Mol. Biol. Cell 12, 3717–3732 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Wang, L., Wible, B. A., Wan, X. & Ficker, E. Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking. J. Pharmacol. Exp. Ther. 320, 525–534 (2007).

    CAS  PubMed  Google Scholar 

  67. Abramowitz, J. et al. Ouabain- and marinobufagenin-induced proliferation of human umbilical vein smooth muscle cells and a rat vascular smooth muscle cell line, A7r5. Circulation 108, 3048–3053 (2003).

    CAS  PubMed  Google Scholar 

  68. Aydemir-Koksoy, A., Abramowitz, J. & Allen, J. C. Ouabain-induced signaling and vascular smooth muscle cell proliferation. J. Biol. Chem. 276, 46605–46611 (2001).

    CAS  PubMed  Google Scholar 

  69. Stenkvist, B. et al. Evidence of a modifying influence of heart glucosides on the development of breast cancer. Anal. Quant. Cytol. 2, 49–54 (1980).

    CAS  PubMed  Google Scholar 

  70. Stenkvist, B. et al. Cardiac glycosides and breast cancer. Lancet 1, 563 (1979).

    CAS  PubMed  Google Scholar 

  71. Stenkvist, B. et al. Cardiac glycosides and breast cancer, revisited. N. Engl. J. Med. 306, 484 (1982). The first epidemiological report on the anticancer effects of cardiac glycosides.

    CAS  PubMed  Google Scholar 

  72. Goldin, A. G. & Safa, A. R. Digitalis and cancer. Lancet 1, 1134 (1984).

    CAS  PubMed  Google Scholar 

  73. Stenkvist, B. Is digitalis a therapy for breast carcinoma? Oncol. Rep. 6, 493–496 (1999).

    CAS  PubMed  Google Scholar 

  74. Haux, J., Klepp, O., Spigset, O. & Tretli, S. Digitoxin medication and cancer; case control and internal dose–response studies. BMC Cancer 1, 11 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Haux, J. Digitoxin is a potential anticancer agent for several types of cancer. Med. Hypotheses 53, 543–548 (1999). The first analytical description of the in vivo antineoplastic properties of digitoxin against several cancer cell lines.

    CAS  PubMed  Google Scholar 

  76. Shiratori, O. Growth inhibitory effect of cardiac glycosides and aglycones on neoplastic cells: in vitro and in vivo studies. Gann 58, 521–528 (1967).

    CAS  PubMed  Google Scholar 

  77. Bielawski, K., Winnicka, K. & Bielawska, A. Inhibition of DNA topoisomerases I and II, and growth inhibition of breast cancer MCF-7 cells by ouabain, digoxin and proscillaridin A. Biol. Pharm. Bull. 29, 1493–1497 (2006).

    CAS  PubMed  Google Scholar 

  78. Lopez-Lazaro, M. et al. Digitoxin inhibits the growth of cancer cell lines at concentrations commonly found in cardiac patients. J. Nat. Prod. 68, 1642–1645 (2005).

    CAS  PubMed  Google Scholar 

  79. McConkey, D. J., Lin, Y., Nutt, L. K., Ozel, H. Z. & Newman, R. A. Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells. Cancer Res. 60, 3807–3812 (2000).

    CAS  PubMed  Google Scholar 

  80. Huang, Y. T., Chueh, S. C., Teng, C. M. & Guh, J. H. Investigation of ouabain-induced anticancer effect in human androgen-independent prostate cancer PC-3 cells. Biochem. Pharmacol. 67, 727–733 (2004).

    CAS  PubMed  Google Scholar 

  81. Yeh, J. Y., Huang, W. J., Kan, S. F. & Wang, P. S. Effects of bufalin and cinobufagin on the proliferation of androgen dependent and independent prostate cancer cells. Prostate 54, 112–124 (2003).

    CAS  PubMed  Google Scholar 

  82. Newman, R. A. et al. Oleandrin-mediated oxidative stress in human melanoma cells. J. Exp. Ther. Oncol. 5, 167–181 (2006).

    CAS  PubMed  Google Scholar 

  83. Newman, R. A. et al. Autophagic cell death of human pancreatic tumor cells mediated by oleandrin, a lipid-soluble cardiac glycoside. Integr. Cancer Ther. 6, 354–364 (2007).

    CAS  PubMed  Google Scholar 

  84. Mijatovic, T. et al. The cardenolide UNBS1450 is able to deactivate nuclear factor κB-mediated cytoprotective effects in human non-small cell lung cancer cells. Mol. Cancer Ther. 5, 391–399 (2006). The first report on UNBS 1450, a novel cardiac glycoside derivative with improved anticancer properties.

    CAS  PubMed  Google Scholar 

  85. Frese, S. et al. 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. 66, 5867–5874 (2006).

    CAS  PubMed  Google Scholar 

  86. Raghavendra, P. B., Sreenivasan, Y., Ramesh, G. T. & Manna, S. K. Cardiac glycoside induces cell death via FasL by activating calcineurin and NF-AT, but apoptosis initially proceeds through activation of caspases. Apoptosis 12, 307–318 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Masuda, Y. et al. Bufalin induces apoptosis and influences the expression of apoptosis-related genes in human leukemia cells. Leuk. Res. 19, 549–556 (1995).

    CAS  PubMed  Google Scholar 

  88. Daniel, D., Susal, C., Kopp, B., Opelz, G. & Terness, P. Apoptosis-mediated selective killing of malignant cells by cardiac steroids: maintenance of cytotoxicity and loss of cardiac activity of chemically modified derivatives. Int. Immunopharmacol. 3, 1791–1801 (2003).

    CAS  PubMed  Google Scholar 

  89. Jing, Y. et al. Selective inhibitory effect of bufalin on growth of human tumor cells in vitro: association with the induction of apoptosis in leukemia HL-60 cells. Jpn. J. Cancer Res. 85, 645–651 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Kawazoe, N., Watabe, M., Masuda, Y., Nakajo, S. & Nakaya, K. Tiam1 is involved in the regulation of bufalin-induced apoptosis in human leukemia cells. Oncogene 18, 2413–2421 (1999).

    CAS  PubMed  Google Scholar 

  91. Watabe, M., Kawazoe, N., Masuda, Y., Nakajo, S. & Nakaya, K. Bcl-2 protein inhibits bufalin-induced apoptosis through inhibition of mitogen-activated protein kinase activation in human leukemia U937 cells. Cancer Res. 57, 3097–3100 (1997).

    CAS  PubMed  Google Scholar 

  92. Kulikov, A., Eva, A., Kirch, U., Boldyrev, A. & Scheiner-Bobis, G. Ouabain activates signaling pathways associated with cell death in human neuroblastoma. Biochim. Biophys. Acta 1768, 1691–1702 (2007).

    CAS  PubMed  Google Scholar 

  93. Johansson, S. et al. Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells. Anticancer Drugs 12, 475–483 (2001).

    CAS  PubMed  Google Scholar 

  94. Van Quaquebeke, E. et al. 2,2,2-Trichloro-N-({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-be nzo[de]isoquinolin- 5-yl}carbamoyl)acetamide (UNBS3157), a novel nonhematotoxic naphthalimide derivative with potent antitumor activity. J. Med. Chem. 50, 4122–4134 (2007).

    CAS  PubMed  Google Scholar 

  95. Johnson, P. H. et al. Multiplex gene expression analysis for high-throughput drug discovery: screening and analysis of compounds affecting genes overexpressed in cancer cells. Mol. Cancer Ther. 1, 1293–1304 (2002).

    CAS  PubMed  Google Scholar 

  96. Smith, J. A., Madden, T., Vijjeswarapu, M. & Newman, R. A. Inhibition of export of fibroblast growth factor-2 (FGF-2) from the prostate cancer cell lines PC3 and DU145 by Anvirzel and its cardiac glycoside component, oleandrin. Biochem. Pharmacol. 62, 469–472 (2001).

    CAS  PubMed  Google Scholar 

  97. Manna, S. K., Sreenivasan, Y. & Sarkar, A. Cardiac glycoside inhibits IL-8-induced biological responses by downregulating IL-8 receptors through altering membrane fluidity. J. Cell Physiol. 207, 195–207 (2006).

    CAS  PubMed  Google Scholar 

  98. Lawrence, T. S. Ouabain sensitizes tumor cells but not normal cells to radiation. Int. J. Radiat. Oncol. Biol. Phys. 15, 953–958 (1988).

    CAS  PubMed  Google Scholar 

  99. Verheye-Dua, F. & Bohm, L. Na+, K+-ATPase inhibitor, ouabain accentuates irradiation damage in human tumour cell lines. Radiat. Oncol. Investig. 6, 109–119 (1998).

    CAS  PubMed  Google Scholar 

  100. Nasu, S., Milas, L., Kawabe, S., Raju, U. & Newman, R. Enhancement of radiotherapy by oleandrin is a caspase-3 dependent process. Cancer Lett. 185, 145–151 (2002).

    CAS  PubMed  Google Scholar 

  101. Inada, A. et al. Anti-tumor promoting activities of natural products. II. Inhibitory effects of digitoxin on two-stage carcinogenesis of mouse skin tumors and mouse pulmonary tumors. Biol. Pharm. Bull. 16, 930–931 (1993).

    CAS  PubMed  Google Scholar 

  102. Afaq, F., Saleem, M., Aziz, M. H. & Mukhtar, H. Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion markers in CD-1 mouse skin by oleandrin. Toxicol. Appl. Pharmacol. 195, 361–369 (2004).

    CAS  PubMed  Google Scholar 

  103. Svensson, A., Azarbayjani, F., Backman, U., Matsumoto, T. & Christofferson, R. Digoxin inhibits neuroblastoma tumor growth in mice. Anticancer Res. 25, 207–212 (2005).

    CAS  PubMed  Google Scholar 

  104. Han, K. Q. et al. Anti-tumor activities and apoptosis-regulated mechanisms of bufalin on the orthotopic transplantation tumor model of human hepatocellular carcinoma in nude mice. World J. Gastroenterol. 13, 3374–3379 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Pathak, S., Multani, A. S., Narayan, S., Kumar, V. & Newman, R. A. Anvirzel, an extract of Nerium oleander, induces cell death in human but not murine cancer cells. Anticancer Drugs 11, 455–463 (2000).

    CAS  PubMed  Google Scholar 

  106. Ahmed, A. et al. Effects of digoxin at low serum concentrations on mortality and hospitalization in heart failure: a propensity-matched study of the DIG trial. Int. J. Cardiol. 123, 138–146 (2008).

    PubMed  Google Scholar 

  107. Mohammadi, K., Kometiani, P., Xie, Z. & Askari, A. Role of protein kinase C in the signal pathways that link Na+/K+-ATPase to ERK1/2. J. Biol. Chem. 276, 42050–42056 (2001).

    CAS  PubMed  Google Scholar 

  108. Gjesdal, K., Feyzi, J. & Olsson, S. B. Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data. Heart 94, 191–196 (2008).

    CAS  PubMed  Google Scholar 

  109. Simpson, R. J. Jr. Assessing the safety of drugs through observational research. Heart 94, 129–130 (2008).

    PubMed  Google Scholar 

  110. Srivastava, M. et al. Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from cystic fibrosis lung epithelial cells. Proc. Natl Acad. Sci. USA 101, 7693–7698 (2004).

    CAS  PubMed  Google Scholar 

  111. Wang, J. K. et al. Cardiac glycosides provide neuroprotection against ischemic stroke: discovery by a brain slice-based compound screening platform. Proc. Natl Acad. Sci. USA 103, 10461–10466 (2006). The first report on the neuroprotective effects of cardiac glycosides against ischaemic stroke.

    CAS  PubMed  Google Scholar 

  112. Pierre, S. V. et al. Ouabain triggers preconditioning through activation of the Na+, K+-ATPase signaling cascade in rat hearts. Cardiovasc. Res. 73, 488–496 (2007).

    CAS  PubMed  Google Scholar 

  113. Piccioni, F., Roman, B. R., Fischbeck, K. H. & Taylor, J. P. A screen for drugs that protect against the cytotoxicity of polyglutamine-expanded androgen receptor. Hum. Mol. Genet. 13, 437–446 (2004).

    CAS  PubMed  Google Scholar 

  114. Nesher, M., Shpolansky, U., Rosen, H. & Lichtstein, D. The digitalis-like steroid hormones: new mechanisms of action and biological significance. Life Sci. 80, 2093–2107 (2007).

    CAS  PubMed  Google Scholar 

  115. Scheiner-Bobis, G. & Schoner, W. A fresh facet for ouabain action. Nature Med. 7, 1288–1289 (2001).

    CAS  PubMed  Google Scholar 

  116. Kaplan, J. H. The sodium pump and hypertension: a physiological role for the cardiac glycoside binding site of the Na, K-ATPase. Proc. Natl. Acad. Sci. USA 102, 15723–15724 (2005).

    CAS  PubMed  Google Scholar 

  117. Dostanic-Larson, I., Van Huysse, J. W., Lorenz, J. N. & Lingrel, J. B. The highly conserved cardiac glycoside binding site of Na, K-ATPase plays a role in blood pressure regulation. Proc. Natl Acad. Sci. USA 102, 15845–15850 (2005).

    CAS  PubMed  Google Scholar 

  118. Kaplan, J. G. Membrane cation transport and the control of proliferation of mammalian cells. Annu. Rev. Physiol. 40, 19–41 (1978).

    CAS  PubMed  Google Scholar 

  119. Espineda, C. et al. Analysis of the Na, K-ATPase alpha- and beta-subunit expression profiles of bladder cancer using tissue microarrays. Cancer 97, 1859–1868 (2003).

    CAS  PubMed  Google Scholar 

  120. Lee, S. et al. Identification of genes differentially expressed between gastric cancers and normal gastric mucosa with cDNA microarrays. Cancer Lett. 184, 197–206 (2002).

    CAS  PubMed  Google Scholar 

  121. Sakai, H. et al. Up-regulation of Na+, K+-ATPase α3-isoform and down-regulation of the α1-isoform in human colorectal cancer. FEBS Lett. 563, 151–154 (2004).

    CAS  PubMed  Google Scholar 

  122. Mijatovic, T. et al. The alpha1 subunit of the sodium pump could represent a novel target to combat non-small cell lung cancers. J. Pathol. 212, 170–179 (2007).

    CAS  PubMed  Google Scholar 

  123. Chen, J. Q. et al. Sodium/potassium ATPase (Na+, K+-ATPase) and ouabain/related cardiac glycosides: a new paradigm for development of anti- breast cancer drugs? Breast Cancer Res. Treat. 96, 1–15 (2006).

    CAS  PubMed  Google Scholar 

  124. Hashimoto, S. et al. Bufalin reduces the level of topoisomerase II in human leukemia cells and affects the cytotoxicity of anticancer drugs. Leuk. Res. 21, 875–883 (1997).

    CAS  PubMed  Google Scholar 

  125. Gatenby, R. A. & Gillies, R. J. Why do cancers have high aerobic glycolysis? Nature Rev. Cancer 4, 891–899 (2004).

    CAS  Google Scholar 

  126. Gatenby, R. A. & Gillies, R. J. Glycolysis in cancer: a potential target for therapy. Int. J. Biochem. Cell Biol. 39, 1358–1366 (2007).

    CAS  PubMed  Google Scholar 

  127. Garber, K. Energy deregulation: licensing tumors to grow. Science 312, 1158–1159 (2006).

    CAS  PubMed  Google Scholar 

  128. Pelicano, H., Martin, D. S., Xu, R. H. & Huang, P. Glycolysis inhibition for anticancer treatment. Oncogene 25, 4633–4646 (2006).

    CAS  PubMed  Google Scholar 

  129. Isidoro, A. et al. Alteration of the bioenergetic phenotype of mitochondria is a hallmark of breast, gastric, lung and oesophageal cancer. Biochem. J. 378, 17–20 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Rhee, S. G., Yang, K. S., Kang, S. W., Woo, H. A. & Chang, T. S. Controlled elimination of intracellular H2O2: regulation of peroxiredoxin, catalase, and glutathione peroxidase via post-translational modification. Antioxid. Redox. Signal. 7, 619–626 (2005).

    CAS  PubMed  Google Scholar 

  131. Paul, R. J., Bauer, M. & Pease, W. Vascular smooth muscle: aerobic glycolysis linked to sodium and potassium transport processes. Science 206, 1414–1416 (1979).

    CAS  PubMed  Google Scholar 

  132. Zavareh, R. B. et al.Inhibition of the sodium/potassium ATPase impairs N-glycan expression and function. Cancer Res. 68, 6688–6697 (2008).

    CAS  Google Scholar 

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Correspondence to Eleftherios P. Diamandis.

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DATABASES

ExPASy Enzyme database 

EC 3.6.3.9

FURTHER INFORMATION

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Glossary

Inotrope

Inotropic agents affect the force of muscular contractions.

Pharmacophore

A molecular framework that carries the essential features responsible for a drug's biological activity.

Angiosperms

The largest phylum of living plants. They develop seeds from ovules contained in ovaries and the seeds are enclosed by fruits that develop from carpels.

Coated pits

A cell-surface depression that is coated with clathrin on its cytoplasmic side and functions mainly in receptor-mediated endocytosis.

N-linked glycan

Sugars attached to the R-group nitrogen (N) of asparagine in the sequence Asn-X-Ser or Asn-X-Thr (X = all amino acids except for proline).

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Prassas, I., Diamandis, E. Novel therapeutic applications of cardiac glycosides. Nat Rev Drug Discov 7, 926–935 (2008). https://doi.org/10.1038/nrd2682

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