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Title
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Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma
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Author
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Abstract
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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 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. |
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Language
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English
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Source (journal)
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The journal of clinical investigation. - New York, N.Y., 1924, currens
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Publication
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New York, N.Y.
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2018
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ISSN
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0021-9738
[print]
1558-8238
[online]
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DOI
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10.1172/JCI99032
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Volume/pages
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128
:8
(2018)
, p. 3341-3355
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ISI
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000440461500020
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Pubmed ID
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29939160
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Full text (Publisher's DOI)
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Full text (open access)
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