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. ua_27687
Investigating the role of ferroptosis in acute liver injury and multiple sclerosis with newly developed chemical tool compounds. ua_36122
Investigation of epigenetic suppressor and enhancer mechanisms of glucocorticoid induced therapy response in leukemia. ua_28892
Quantitative proteomic characterization of cellular targets of withaferin A involved in cancer therapy chemosensitisation in B-cell chronic leukemia cells. ua_27655
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 27.06.2018
Last edited 15.11.2022
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