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Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma.
J. Clin. Invest. 128, 3341-3355 (2018)
Publ. Version/Full Text Research data DOI
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Drug Therapy ; Nanotechnology ; Neurological Disorders ; Neuroscience ; Oncology; Cell-death; Cancer-cells; Oxidative Stress; Withania-somnifera; Tumor-growth; Iron; Therapy; Pathway; Expression; Gpx4
ISSN (print) / ISBN 0021-9738
Quellenangaben Volume: 128, Issue: 8, Pages: 3341-3355
Publisher American Society of Clinical Investigation
Publishing Place 2015 Manchester Rd, Ann Arbor, Mi 48104 Usa
Institute(s) Institute of Developmental Genetics (IDG)