Quo vadis Cardiac Glycoside Research?

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.

Evidence for tissue‐specific defence‐offence interactions between milkweed and its community of specialized herbivores

“…We found that more polar cardenolides are dominant in seeds, which contrasts with the more diverse and less polar composition in other tissues (Figure S1), the latter of which consistently showed greater inhibition against all insects. Structure-affinity relationships between cardenolides and the amino acid residues of the sodium pump seem to be driven by polar interactions of hydrogen bonds with the hydroxyl groups in the steroidal skeleton of cardenolides (Bejcek et al, 2021;Laursen et al, 2013). In other words, more polar compounds seem to have greater affinity to a more polar enzyme.…”

Research Progress in Pharmacological Activities and Applications of Cardiotonic Steroids

“…The expression of the NKA subunit in some cancer cells may be altered compared with healthy tissues (Mijatovic et al, 2007). Studies have shown that the antitumor effect of CTS is mainly through the non-transport function of NKA, that is, the activation of signal transduction function (Bejček et al, 2021). The specific antitumor efficacy and mechanism of action need further study.…”

Evidence for Cardiac Glycosides in Foliage of Colorado Potato Beetle-Resistant Solanum okadae

“…Cardiac glycosides are naturally occurring compounds found in plants and animals, where they serve as a defense mechanism . Cardiac glycosides have structures derived from the steroid skeleton . The skeleton typically consists of three 6-membered carbon rings and one 5-membered ring (Figure ), with a lactone ring at the C-17 position and a sugar moiety at C-3 .…”