Effect Of 21‐Benzylidene Digoxin On Cancer Cells: A Cardenolide With No Inhibitory Effect On Na,K‐ATPase Activity

Abstract

Recently, new data began to consider cardiac glycoside as a potential antitumor drug. We synthesized 21‐benzylidene digoxin (21‐BD) through an aldol condensation of digoxin lactone ring. Molecular docking was performed to assess the main interactions between cardiac glycosides and Na,K‐ATPase, demonstrating a more stable binding energy for 21‐BD, compared with digoxin. Therefore, we used HeLa and RKO cancer cell lines after their exposure to cardiac glycosides to asses the cell viability as to cytotoxicity and proliferative ability. On HeLa cells, digoxin presented an IC50 = 1,47 μM, whereas 21‐BD presented an IC50 = 56,16 μM. Nevertheless, on RKO cells, digoxin presented an IC50 = 0,46 μM and 21‐BD presented an IC50 = 54,36 μM. Cometa assay showed DNA damage upon 20 μM of both cardiac glycosides. The treatment of cells with 21‐BD for 48h caused an increase of Na,K‐ATPase activity, whereas digoxin caused a decrease on enzyme activity. However, 21‐BD did not cause inhibition of Na,K‐ATPase of a membrane preparation from rat cerebral hemisphere. In attempt to avoid the 21‐BD effect though estrogen receptor, the pre‐treatment with tamoxifen did not interrupted the DGB1 effect. Thus, these data demonstrate that this new glycoside has a different mechanism of action then digoxin, and it can be an important tool to study the enzyme.Supported by: FAPEMIG, CNPq and CAPES