Abstract
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.
Highlights
Active secondary metabolites occur in almost any living system, from unicellular organisms to fungi, plants, and animals
cardiac glycosides (CGs) as plant toxins have been known to mankind for centuries and during that time, they have built up a solid place in pharmacy as drugs for the treatment of heart failure and arrhythmias due to their positive inotropic effect on the heart muscle cells
The first part of this review article focuses on the occurrence of CGs and the optimization of their production, which is still a major challenge, as CGs are currently still isolated from plants, unlike many other drugs that are produced by organic synthesis or microbial biotechnology
Summary
Active secondary metabolites occur in almost any living system, from unicellular organisms to fungi, plants, and animals. The best known is the production by plants of the Digitalis genus (Scrophulariaceae), from which the most important representatives of this group are mostly isolated, namely digoxin (Dg) and digitoxin (Dgt) Both substances are well-established drugs for the treatment of heart failure and cardiac arrhythmias, even though they have a relatively narrow therapeutic window that limits their use [8]. Ca2+ ions, which serve as mediators of muscle contraction, are involved in signaling pathways that lead to cell death by apoptosis The latter fact is the reason why CGs are currently being studied as possible drugs for cancer treatment. The role of CGs in the regulation of blood pressure and, more recently, their antiviral effects were discovered
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