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Discovery of Sulforaphane as an Inducer of Ferroptosis in U-937 Leukemia Cells: Expanding Its Anticancer Potential.

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.

SUBMITTER: Greco G

PROVIDER: S-EPMC8750507 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Discovery of Sulforaphane as an Inducer of Ferroptosis in U-937 Leukemia Cells: Expanding Its Anticancer Potential.

Greco Giulia G Schnekenburger Michael M Catanzaro Elena E Turrini Eleonora E Ferrini Fabio F Sestili Piero P Diederich Marc M Fimognari Carmela C

Cancers 20211224 1

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 ...[more]

PMID: 35008240

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Project description:IntroductionOxyresveratrol (ORes) exhibits significant anticancer activity, particularly against breast cancer. However, its exact mechanism of action (MOA) remains unclear. This study aimed to investigate the pharmacological activity and underlying MOA.MethodsThe inhibitory effect of ORes on breast cancer cell growth was confirmed, and the effective concentrations were determined for further experiments. Gene expression profiles (GEPs) were collected from MDA-MB-231 cells treated with ORes at varying concentrations using HTS2. Bioinformatics tools were used to predict the anticancer activity and MOA of ORes. Ferroptosis markers (ferrous ions, reactive oxygen species, lipid peroxidation, and GPX4 expression) were assessed, and mitochondrial morphology was observed. The effect of ORes on tumour growth was evaluated in vivo, along with the analysis of ferroptosis in tissues. The MOA was explored using L1000, Drug Gene DataBase (DGDB), and Western blotting analyses.ResultsORes significantly reduces breast cancer cell viability and proliferation in a concentration-dependent manner, with IC50 values of 104.8 μM, 150.2 μM, and 143.6 μM in MDA-MB-231, BT-549, and 4T1 cells, respectively. GEPs induced by ORes were significantly enriched in the ferroptosis and PI3K/AKT signalling pathways. ORes inhibited breast cancer cell growth, increased intracellular ferrous ion levels, reactive oxygen species, and lipid peroxidation, and induced ferroptosis-related mitochondrial alterations. These effects were associated with decreased GPX4 expression and suppression of EGFR, phosphorylated PI3K, and phosphorylated AKT. ORes inhibited tumour growth, enhanced iron deposition, and reduced GPX4 expression in tumour tissues in vivo. Notably, treatment with the ferroptosis inhibitor ferrostatin-1 (Ferr-1) attenuated the anticancer effects of ORes, confirming the pivotal role of ferroptosis in ORes-mediated breast cancer inhibition.ConclusionORes inhibits breast cancer cell growth by inducing ferroptosis through suppression of the EGFR/PI3K/AKT/GPX4 signalling axis. This study suggests that ORes holds promise as a potential therapeutic agent for breast cancer and warrants further investigation into its clinical applications and potential integration into existing treatment regimens.

Dataset Information

Discovery of Sulforaphane as an Inducer of Ferroptosis in U-937 Leukemia Cells: Expanding Its Anticancer Potential.

Publications

Discovery of Sulforaphane as an Inducer of Ferroptosis in U-937 Leukemia Cells: Expanding Its Anticancer Potential.

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