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  • Review Article
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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.

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Correspondence to Eleftherios P. Diamandis.

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DATABASES

ExPASy Enzyme database 

EC 3.6.3.9

FURTHER INFORMATION

ChemBank database

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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