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Hassannia, B.* ; Wiernicki, B.* ; Ingold, I. ; Qu, F.* ; Van Herck, S.* ; Tyurina, Y.Y.* ; Bayır, H.* ; Abhari, B.A.* ; Angeli, J.P.F.* ; Choi, S.M.* ; Meul, E.* ; Heyninck, K.* ; Declerck, K.* ; Chirumamilla, C.S.* ; Lahtela-Kakkonen, M.* ; Van Camp, G.* ; Krysko, D.V.* ; Ekert, P.G.* ; Fulda, S.* ; De Geest, B.G.* ; Conrad, M. ; Kagan, V.E.* ; Berghe, W.V.* ; Vandenabeele, P.* ; Berghe, T.V.*

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
Open Access Green as soon as Postprint is submitted to ZB.
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
e-ISSN 1558-8238
Quellenangaben Volume: 128, Issue: 8, Pages: 3341-3355 Article Number: , Supplement: ,
Publisher American Society of Clinical Investigation
Publishing Place 2015 Manchester Rd, Ann Arbor, Mi 48104 Usa
Reviewing status