21-benzylidene digoxin decreases proliferation by inhibiting the egfr/erk signaling pathway and induces apoptosis in hela cells

Publication date: Available online 6 December 2019Source: SteroidsAuthor(s): Marco Túlio C. Pessôa, Jéssica M.M. Valadares, Sayonarah C. Rocha, Simone C. Silva, Jeff P. McDermott, Gladis Sánchez, Fernando P. Varotti, Cristóforo Scavone, Rosy I.M.A. Ribeiro, José A.F.P. Villar, Gustavo Blanco, Leandro A. BarbosaAbstractCardiotonic steroids (CTS) are agents traditionally known for their capacity to bind to the Na,K-ATPase (NKA), affecting the ion transport and the contraction of the heart. Natural CTS have been shown to also have effects on cell signaling pathways. With the goal of developing a new CTS derivative , we synthesized a new digoxin derivative, 21-benzylidene digoxin (21-BD). Previously, we have shown that this compound binds to NKA and has cytotoxic actions on cancer, but not on normal cells. Here, we further studied the mechanisms of actions of 21-BD. Working with HeLa cells, we found that 21-BD decreases the basal, as well as the insulin stimulated proliferation. 21-BD reduces phosphorylation of the epidermal growth factor receptor (EGFR) and extracellular-regulated kinase (ERK), which are involved in pathways that stimulate cell proliferation. In addition, 21-BD promotes apoptosis, which is mediated by the translocation of Bax from the cytosol to mitochondria and the release of mitochondrial cytochrome c to the cytosol. 21-BD also activated caspases-8, -9 and -3, and induced the cleavage of poly (ADP-ribose) polymerase-1 (PARP-1). Altogether, these results ...
Source: Steroids - Category: Drugs & Pharmacology Source Type: research