21-Benzylidene digoxin decreases proliferation by inhibiting the EGFR/ERK signaling pathway and induces apoptosis in HeLa cells
| Autor: | José A.F.P. Villar, Rosy Iara Maciel de Azambuja Ribeiro, Gustavo Blanco, Jessica M M Valadares, Jeffrey McDermott, Fernando de Pilla Varotti, Cristoforo Scavone, Simone C. Silva, Sayonarah C. Rocha, Leandro A. Barbosa, Marco Túlio C. Pessôa, Gladis Sánchez |
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| Rok vydání: | 2020 |
| Předmět: |
MAPK/ERK pathway
Digoxin Cell Survival Clinical Biochemistry Molecular Conformation Antineoplastic Agents Apoptosis 030209 endocrinology & metabolism Mitochondrion Biochemistry Article HeLa Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Endocrinology Tumor Cells Cultured Humans Extracellular Signal-Regulated MAP Kinases Protein Kinase Inhibitors Molecular Biology Cell Proliferation Pharmacology Dose-Response Relationship Drug biology Cell growth Kinase Chemistry Organic Chemistry biology.organism_classification Mitochondria Cell biology ErbB Receptors Cytosol 030220 oncology & carcinogenesis Phosphorylation Drug Screening Assays Antitumor GLICOSÍDEOS HeLa Cells Signal Transduction |
| Zdroj: | Steroids Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 0039-128X |
| Popis: | Cardiotonic 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 show that the new compound that we have synthesized exerts cytotoxic actions on HeLa cells by inhibition of cell proliferation and the activation of both the extrinsic and intrinsic apoptotic pathways. These results support the relevance of the cardiotonic steroid scaffold as modulators of cell signaling pathways and potential agents for their use in cancer. |
| Databáze: | OpenAIRE |
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