Apoptosis and necroptosis induced by stenodactylin in neuroblastoma cells can be completely prevented through caspase inhibition plus catalase or necrostatin-1
| Autor: | Andrea Bolognesi, Maria Giulia Battelli, Manuela Pedrazzi, Letizia Polito, Daniele Mercatelli, Massimo Bortolotti |
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| Přispěvatelé: | Polito, Letizia, Bortolotti, Massimo, Pedrazzi, Manuela, Mercatelli, Daniele, Battelli, Maria Giulia, Bolognesi, Andrea |
| Jazyk: | angličtina |
| Předmět: |
0301 basic medicine
Programmed cell death Indoles Necroptosis Pharmaceutical Science Apoptosis medicine.disease_cause Amino Acid Chloromethyl Ketones 03 medical and health sciences Anti-cancer drug Neuroblastoma Cell Line Tumor Lectins Drug Discovery medicine Humans Plant toxin Cytotoxicity N-Glycosyl Hydrolases Caspase chemistry.chemical_classification Pharmacology Reactive oxygen species biology Cell Death Drug Discovery3003 Pharmaceutical Science Ribosome-inactivating protein Imidazoles Apoptosi Complementary and Alternative Medicine2708 Dermatology Catalase Molecular biology Caspase Inhibitors Cell biology 030104 developmental biology chemistry Complementary and alternative medicine Oxidative stress Caspases biology.protein Oxidative stre Molecular Medicine Reactive Oxygen Species |
| Zdroj: | Phytomedicine. (1):32-41 |
| ISSN: | 0944-7113 |
| DOI: | 10.1016/j.phymed.2015.11.006 |
| Popis: | Background Stenodactylin is a highly toxic plant lectin purified from the caudex of Adenia stenodactyla , with molecular structure, intracellular routing and enzyme activity similar to those of ricin, a well-known type 2 ribosome-inactivating protein. However, in contrast with ricin, stenodactylin is retrogradely transported not only in peripheral nerves but also in the central nervous system. Purpose Stenodactylin properties make it a potential candidate for application in neurobiology and in experimental therapies against cancer. Thus, it is necessary to better clarify the toxic activity of this compound. Study design We investigated the mechanism of stenodactylin-induced cell death in the neuroblastoma-derived cell line, NB100, evaluating the implications of different death pathways and the involvement of oxidative stress. Methods Stenodactylin cytotoxicity was determined by evaluating protein synthesis and other viability parameters. Cell death pathways and oxidative stress were analysed through flow cytometry and microscopy. Inhibitors of apoptosis, oxidative stress and necroptosis were tested to evaluate their protective effect against stenodactylin cytotoxicity. Results Stenodactylin efficiently blocked protein synthesis and reduced the viability of neuroblastoma cells at an extremely low concentration and over a short time (1 pM, 24 h). Stenodactylin induced the strong and rapid activation of apoptosis and the production of free radicals. Here, for the first time, a complete and long lasting protection from the lethal effect induced by a toxic type 2 ribosome-inactivating protein has been obtained by combining the caspase inhibitor Z-VAD-fmk, to either the hydrogen peroxide scavenger catalase or the necroptotic inhibitor necrostatin-1. Conclusion In respect to stenodactylin cytotoxicity, our results: (i) confirm the high toxicity to nervous cells, (ii) indicate that multiple cell death pathways can be induced, (iii) show that apoptosis is the main death pathway, (iv) demonstrate the involvement of necroptosis and (v) oxidative stress. |
| Databáze: | OpenAIRE |
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