Cargando…
Discovery of Sulforaphane as an Inducer of Ferroptosis in U-937 Leukemia Cells: Expanding Its Anticancer Potential
SIMPLE SUMMARY: Ferroptosis and necroptosis are two non-apoptotic programmed cell death pathways with increasing therapeutic potential. The isothiocyanate sulforaphane (SFN) is a well-known naturally derived anticancer compound with remarkable pro-apoptotic activity. Its ability to promote non-apopt...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750507/ https://www.ncbi.nlm.nih.gov/pubmed/35008240 http://dx.doi.org/10.3390/cancers14010076 |
_version_ | 1784631476240777216 |
---|---|
author | Greco, Giulia Schnekenburger, Michael Catanzaro, Elena Turrini, Eleonora Ferrini, Fabio Sestili, Piero Diederich, Marc Fimognari, Carmela |
author_facet | Greco, Giulia Schnekenburger, Michael Catanzaro, Elena Turrini, Eleonora Ferrini, Fabio Sestili, Piero Diederich, Marc Fimognari, Carmela |
author_sort | Greco, Giulia |
collection | PubMed |
description | SIMPLE SUMMARY: Ferroptosis and necroptosis are two non-apoptotic programmed cell death pathways with increasing therapeutic potential. The isothiocyanate sulforaphane (SFN) is a well-known naturally derived anticancer compound with remarkable pro-apoptotic activity. Its ability to promote non-apoptotic cell death mechanisms remains poorly investigated. This work discovered that SFN activates apoptosis and ferroptosis dose-dependently in acute myeloid leukemia cells. At lower concentrations, SFN induces caspase-dependent apoptosis. At higher concentrations, ferroptosis is activated and accompanied by the depletion of intracellular glutathione (GSH) and decreased GSH peroxidase 4 protein expression levels. Necroptosis, instead, is not involved in SFN-induced cell death. Considering that cancer cells resist pro-apoptotic treatments, SFN’s ability to induce different types of cell death delineates it as a promising anticancer agent. ABSTRACT: In recent years, natural compounds have emerged as inducers of non-canonical cell death. The isothiocyanate sulforaphane (SFN) is a well-known natural anticancer compound with remarkable pro-apoptotic activity. Its ability to promote non-apoptotic cell-death mechanisms remains poorly investigated. This work aimed to explore the capacity of SFN to induce non-apoptotic cell death modalities. SFN was tested on different acute myeloid leukemia cell lines. The mechanism of cell death was investigated using a multi-parametric approach including fluorescence microscopy, western blotting, and flow cytometry. SFN triggered different cell-death modalities in a dose-dependent manner. At 25 μM, SFN induced caspase-dependent apoptosis and at 50 μM ferroptosis was induced through depletion of glutathione (GSH), decreased GSH peroxidase 4 protein expression, and lipid peroxidation. In contrast, necroptosis was not involved in SFN-induced cell death, as demonstrated by the non-significant increase in phosphorylation of receptor-interacting protein kinase 3 and phosphorylation of the necroptotic effector mixed lineage kinase domain-like pseudokinase. Taken together, our results suggest that the antileukemic activity of SFN can be mediated via both ferroptotic and apoptotic cell death modalities. |
format | Online Article Text |
id | pubmed-8750507 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-87505072022-01-12 Discovery of Sulforaphane as an Inducer of Ferroptosis in U-937 Leukemia Cells: Expanding Its Anticancer Potential Greco, Giulia Schnekenburger, Michael Catanzaro, Elena Turrini, Eleonora Ferrini, Fabio Sestili, Piero Diederich, Marc Fimognari, Carmela Cancers (Basel) Article SIMPLE SUMMARY: Ferroptosis and necroptosis are two non-apoptotic programmed cell death pathways with increasing therapeutic potential. The isothiocyanate sulforaphane (SFN) is a well-known naturally derived anticancer compound with remarkable pro-apoptotic activity. Its ability to promote non-apoptotic cell death mechanisms remains poorly investigated. This work discovered that SFN activates apoptosis and ferroptosis dose-dependently in acute myeloid leukemia cells. At lower concentrations, SFN induces caspase-dependent apoptosis. At higher concentrations, ferroptosis is activated and accompanied by the depletion of intracellular glutathione (GSH) and decreased GSH peroxidase 4 protein expression levels. Necroptosis, instead, is not involved in SFN-induced cell death. Considering that cancer cells resist pro-apoptotic treatments, SFN’s ability to induce different types of cell death delineates it as a promising anticancer agent. ABSTRACT: In recent years, natural compounds have emerged as inducers of non-canonical cell death. The isothiocyanate sulforaphane (SFN) is a well-known natural anticancer compound with remarkable pro-apoptotic activity. Its ability to promote non-apoptotic cell-death mechanisms remains poorly investigated. This work aimed to explore the capacity of SFN to induce non-apoptotic cell death modalities. SFN was tested on different acute myeloid leukemia cell lines. The mechanism of cell death was investigated using a multi-parametric approach including fluorescence microscopy, western blotting, and flow cytometry. SFN triggered different cell-death modalities in a dose-dependent manner. At 25 μM, SFN induced caspase-dependent apoptosis and at 50 μM ferroptosis was induced through depletion of glutathione (GSH), decreased GSH peroxidase 4 protein expression, and lipid peroxidation. In contrast, necroptosis was not involved in SFN-induced cell death, as demonstrated by the non-significant increase in phosphorylation of receptor-interacting protein kinase 3 and phosphorylation of the necroptotic effector mixed lineage kinase domain-like pseudokinase. Taken together, our results suggest that the antileukemic activity of SFN can be mediated via both ferroptotic and apoptotic cell death modalities. MDPI 2021-12-24 /pmc/articles/PMC8750507/ /pubmed/35008240 http://dx.doi.org/10.3390/cancers14010076 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Greco, Giulia Schnekenburger, Michael Catanzaro, Elena Turrini, Eleonora Ferrini, Fabio Sestili, Piero Diederich, Marc Fimognari, Carmela Discovery of Sulforaphane as an Inducer of Ferroptosis in U-937 Leukemia Cells: Expanding Its Anticancer Potential |
title | Discovery of Sulforaphane as an Inducer of Ferroptosis in U-937 Leukemia Cells: Expanding Its Anticancer Potential |
title_full | Discovery of Sulforaphane as an Inducer of Ferroptosis in U-937 Leukemia Cells: Expanding Its Anticancer Potential |
title_fullStr | Discovery of Sulforaphane as an Inducer of Ferroptosis in U-937 Leukemia Cells: Expanding Its Anticancer Potential |
title_full_unstemmed | Discovery of Sulforaphane as an Inducer of Ferroptosis in U-937 Leukemia Cells: Expanding Its Anticancer Potential |
title_short | Discovery of Sulforaphane as an Inducer of Ferroptosis in U-937 Leukemia Cells: Expanding Its Anticancer Potential |
title_sort | discovery of sulforaphane as an inducer of ferroptosis in u-937 leukemia cells: expanding its anticancer potential |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750507/ https://www.ncbi.nlm.nih.gov/pubmed/35008240 http://dx.doi.org/10.3390/cancers14010076 |
work_keys_str_mv | AT grecogiulia discoveryofsulforaphaneasaninducerofferroptosisinu937leukemiacellsexpandingitsanticancerpotential AT schnekenburgermichael discoveryofsulforaphaneasaninducerofferroptosisinu937leukemiacellsexpandingitsanticancerpotential AT catanzaroelena discoveryofsulforaphaneasaninducerofferroptosisinu937leukemiacellsexpandingitsanticancerpotential AT turrinieleonora discoveryofsulforaphaneasaninducerofferroptosisinu937leukemiacellsexpandingitsanticancerpotential AT ferrinifabio discoveryofsulforaphaneasaninducerofferroptosisinu937leukemiacellsexpandingitsanticancerpotential AT sestilipiero discoveryofsulforaphaneasaninducerofferroptosisinu937leukemiacellsexpandingitsanticancerpotential AT diederichmarc discoveryofsulforaphaneasaninducerofferroptosisinu937leukemiacellsexpandingitsanticancerpotential AT fimognaricarmela discoveryofsulforaphaneasaninducerofferroptosisinu937leukemiacellsexpandingitsanticancerpotential |