Publication
Title
Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma
Author
Abstract
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 factorlike 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.
Language
English
Source (journal)
The journal of clinical investigation. - New York, N.Y., 1924, currens
Publication
New York, N.Y. : 2018
ISSN
0021-9738 [print]
1558-8238 [online]
Volume/pages
128:8(2018), p. 3341-3355
ISI
000440461500020
Pubmed ID
29939160
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
Project info
Identification, lead optimization and validation of necroptosis inhibitors.
Investigating the role of ferroptosis in acute liver injury and multiple sclerosis with newly developed chemical tool compounds.
Investigation of epigenetic suppressor and enhancer mechanisms of glucocorticoid induced therapy response in leukemia.
Quantitative proteomic characterization of cellular targets of withaferin A involved in cancer therapy chemosensitisation in B-cell chronic leukemia cells.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 27.06.2018
Last edited 06.09.2021
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