The mechanistic role of cardiac glycosides in DNA damage response and repair signaling

Abstract

Cardiac glycosides (CGs) are a class of bioactive organic compounds well-known for their application in treating heart disease despite a narrow therapeutic window. Considerable evidence has demonstrated the potential to repurpose CGs for cancer treatment. Chemical modification of these CGs has been utilized in attempts to increase their anti-cancer properties; however, this has met limited success as their mechanism of action is still speculative. Recent studies have identified the DNA damage response (DDR) pathway as a target of CGs. DDR serves to coordinate numerous cellular pathways to initiate cell cycle arrest, promote DNA repair, regulate replication fork firing and protection, or induce apoptosis to avoid the survival of cells with DNA damage or cells carrying mutations. Understanding the modus operandi of cardiac glycosides will provide critical information to better address improvements in potency, reduced toxicity, and the potential to overcome drug resistance. This review summarizes recent scientific findings of the molecular mechanisms of cardiac glycosides affecting the DDR signaling pathway in cancer therapeutics from 2010 to 2022. We focus on the structural and functional differences of CGs toward identifying the critical features for DDR targeting of these agents.

Keywords: Bufadienolide; Cancer therapeutics; Cardenolide; Cytotoxicity; Structure–activity relationships.

Fig. 1

a Conventional structural framework of CGs and b Structural scaffold of glycosides considered

Fig. 2

Summary of glycosides discussed in manuscript

Fig. 3

[1] DDR sensors and signaling. DNA damage including DSBs and SSBs, have been found following treatments with different CGs. (yellow = increased expression, pink = decreased expression) As such, upstream DNA repair proteins including PARP, ATM, ATR, and DNA-PK are recruited by DNA damage sensors RPA, MRN and Ku protein which triggers DDR signalling

Fig. 4

[1] CGs and ROS signaling. CGs trigger the production of ROS and DNA damage. A culmination of all or part of these consequences activate different signaling pathways; PI3K (purple), p53 (green) and JNK (blue)