Digitoxin and its analogs as novel cancer therapeutics

Cardiac glycosides (CGs) are a large family of chemical compounds found in several plants and animal species [1]. Plants containing CGs were used for more than 1500 years as diuretics, emetics, abortifacients, antineoplastics, and heart tonics [2]. In the 18th century, English physician and scientist William Withering discovered that a patient with congestive heart failure, "dropsy", improved after administering foxglove extract (Digitalis purpurea L.) [3]. Since then, many CGs have been isolated and their pharmacological effects have been tested; subsequently, CGs were used for treating congestive heart failure, cardiac arrhythmias, and atrial fibrillation [4,5].Generally, CGs share a common structural motif with a steroidal nucleus, a sugar moiety at position 3 (C3), and a lactone moiety at position 17 (C17) [1]. Figure 1 shows the common structural motif of CGs. The steroidal nucleus is the core structure of CG and is considered to be the active pharmacophoric moiety [6]. CGs also show an A/B and C/D cis-conformation that is different from mineralocorticoids, glycocorticoids, or sex hormones known to show trans-confirmation [6]. The presence of sugars at position 3 on the steroid ring significantly affects the pharmacological profile of each glycoside [7,8]. Free aglycones, for instance, show faster and less complex absorption and metabolism compared to their glycosylated counterparts [7]. Additionally, the type of sugar attached to the steroidal nucleus changes the potency of CG compounds [8,9].It is well established that CGs inhibit Na+/K+-ATPase and increases intracellular sodium ions [10]. The Na+/K+-ATPase is a P-type pump that actively transports potassium ions inside and sodium ions outside cells in a 2:3 stoichiometry [11]. Such activity keeps intracellular sodium levels low, thus initiating and sustaining adequate electrochemical gradient across the plasma membrane [11]. Appropriate electrochemical gradient is essential for vital cellular processes such