Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 128, Issue 8, Pages 3341-3355Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI99032
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Funding
- UGent Special Research Fund [BOF14/GOA/019]
- Methusalem grant of PV
- Belgian grants [IAP 7/32, EOS 30826052]
- Flemish grants (Research Foundation Flanders) [FWO G.0875.11, FWO G.0973.11, FWO G.0A45.12N, FWO G.0787.13N, FWO G.0C31.14N, FWO G.0E04.16N, G.0C76.18N, G.0B71.18N, FWO G.079614N, G.059713N]
- Flemish grants (Methusalem grants) [BOF09/01M00709, BOF16/MET_V/007]
- Ghent University (Multidisciplinary Research Partnerships, GROUP-ID consortium)
- Foundation against Cancer [F94/2012-188 and FAF-F/2016/865]
- VIB
- COST Action - Epigenetic Chemical Biology (EPICHEM) [CM1406]
- BOF grant from Ghent University [09/DOS/022]
- NIH [NS076511, NS061817, U19 AI068021, P01 HL114453, ES020693, CA165065]
- Children's Cancer Foundation
- Steven Walter Children's Cancer Foundation
- Junior Group Leader program from the Rudolf Virchow Center, University of Wurzburg
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High-risk neuroblastoma is a devastating malignancy with very limited therapeutic options. Here, we identify withaferin A (WA) as a natural ferroptosis-inducing agent in neuroblastoma, which acts through a novel double-edged mechanism. WA dose-dependently either activates the nuclear factor-like 2 pathway through targeting of Kelch-like ECH-associated protein 1 (noncanonical ferroptosis induction) or inactivates glutathione peroxidase 4 (canonical ferroptosis induction). Noncanonical ferroptosis induction is characterized by an increase in intracellular labile Fe(II) upon excessive activation of heme oxygenase-1, which is sufficient to induce ferroptosis. This double-edged mechanism might explain the superior efficacy of WA as compared with etoposide or cisplatin in killing a heterogeneous panel of high-risk neuroblastoma cells, and in suppressing the growth and relapse rate of neuroblastoma xenografts. Nano-targeting of WA allows systemic application and suppressed tumor growth due to an enhanced accumulation at the tumor site. Collectively, our data propose a novel therapeutic strategy to efficiently kill cancer cells by ferroptosis.
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