Abstract
Cardiotonic steroids are used to treat heart failure and arrhythmia and have promising anticancer effects. The prototypic cardiotonic steroid ouabain may also be a hormone that modulates epithelial cell adhesion. Cardiotonic steroids consist of a steroid nucleus and a lactone ring, and their biological effects depend on the binding to their receptor, Na,K-ATPase, through which, they inhibit Na+ and K+ ion transport and activate of several intracellular signaling pathways. In this study, we added a styrene group to the lactone ring of the cardiotonic steroid digoxin, to obtain 21-benzylidene digoxin (21-BD), and investigated the effects of this synthetic cardiotonic steroid in different cell models. Molecular modeling indicates that 21-BD binds to its target Na,K-ATPase with low affinity, adopting a different pharmacophoric conformation when bound to its receptor than digoxin. Accordingly, 21-DB, at relatively high µM amounts inhibits the activity of Na,K-ATPase α1, but not α2 and α3 isoforms. In addition, 21-BD targets other proteins outside the Na,K-ATPase, inhibiting the multidrug exporter Pdr5p. When used on whole cells at low µM concentrations, 21-BD produces several effects, including: 1) up-regulation of Na,K-ATPase expression and activity in HeLa and RKO cancer cells, which is not found for digoxin, 2) cell specific changes in cell viability, reducing it in HeLa and RKO cancer cells, but increasing it in normal epithelial MDCK cells, which is different from the response to digoxin, and 3) changes in cell-cell interaction, altering the molecular composition of tight junctions and elevating transepithelial electrical resistance of MDCK monolayers, an effect previously found for ouabain. These results indicate that modification of the lactone ring of digoxin provides new properties to the compound, and shows that the structural change introduced could be used for the design of cardiotonic steroid with novel functions.
Highlights
Cardiotonic steroids are common substances in the plant kingdom that confer a competitive advantage against depredation, either to the plant that synthesizes them, or to the animals that accumulates them from the diet [1]
These compounds frequently have a sugar attached at position 3b of the steroidal nucleus, for which they are commonly known as cardiac glycosides
The re-dock structure obtained with the software Autodock Vina, shows that the refined and the crystallographic ligand share the same conformation at the active site, with a root mean square deviation value of 2.24 Afor the best solution, which indicated the accuracy of the methodology used
Summary
Cardiotonic steroids are common substances in the plant kingdom that confer a competitive advantage against depredation, either to the plant that synthesizes them, or to the animals that accumulates them from the diet [1]. Some experimental evidence shows that animals can endogenously synthesize cardiac steroids and that these substances play an important role in the regulation of blood pressure, cell proliferation and cell death [2,3]. The basic structure of cardiotonic steroids consists of a steroid backbone with a cis/trans/cis configuration and a lactone moiety at position 17b, known as the aglycone. These compounds frequently have a sugar attached at position 3b of the steroidal nucleus, for which they are commonly known as cardiac glycosides. Digitoxin, is more lipophilic, shows strong binding to plasma proteins, is almost entirely metabolized in the liver and exhibits a very long half-life. Digoxin displays weak binding to plasma proteins, is not extensively metabolized and is excreted in a primarily unaltered form by the kidneys [2,3]
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