Digitoxin and its analogs as novel cancer therapeutics

Abstract

A growing body of evidence indicates that digitoxin cardiac glycoside is a promising anticancer agent when used at therapeutic concentrations. Digitoxin has a prolonged half-life and a well-established clinical profile. New scientific avenues have shown that manipulating the chemical structure of the saccharide moiety of digitoxin leads to synthetic analogs with increased cytotoxic activity. However, the anticancer mechanism of digitoxin or synthetic analogs is still subject to study while concerns about digitoxin's cardiotoxicity preclude its clinical application in cancer therapeutics. This review focuses on digitoxin and its analogs, and their cytotoxicity against cancer cells. Moreover, a new perspective on the pharmacological aspects of digitoxin and its analogs is provided to emphasize new research directions for developing potent chemotherapeutic drugs.

Figure 1

Structural characteristics of CGs. The common structural motif of a CG molecule is characterized by a steroidal nucleus, a lactone moiety at C17, and a saccharide moiety at C3 linked to the steroidal nucleus by a glycosidic linkage.

Figure 2

Effects of digitoxin on Na⁺/K⁺-ATPase at micromolar and nanomolar concentrations. (A) Old theory model summarizes the effect of digitoxin at 0.5-5 μM concentrations. (B) New theory model summarizes digitoxin's effect at 0.01-0.1 μM concentrations.

Figure 3

The structure of novel digitoxin analogs. (A) The common structural motif of a neoglycoside molecule developed by Langenhan et al. and characterized by a tertiary amine bond linking the saccharide moiety to the steroidal nucleus. (B) The common structural motif of a digitoxin O-saccharide molecule developed by O'Doherty et al. and characterized by an ether bond linking the saccharide moiety to the steroidal nucleus.

Figure 4

Digitoxin modulates Na⁺/K⁺-ATPase signalosome and inhibits the transcriptional activity of AP-1 and NF-κB which mediate the expression of cancer-specific cycle regulatory genes such as cyclin B1, cdc2, Chk1, Chk2, and surviving.