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- Title
Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma.
- Authors
Hassannia, Behrouz; Wiernicki, Bartosz; Ingold, Irina; Feng Qu; Van Herck, Simon; Tyurina, Yulia Y.; BayıR, Hülya; Abhari, Behnaz A.; Friedmann Angeli, Jose Pedro; Sze Men Choi; Meul, Eline; Heyninck, Karen; Declerck, Ken; Chirumamilla, Chandra Sekhar; Lahtela-Kakkonen, Maija; Van Camp, Guy; Krysko, Dmitri V.; Ekert, Paul G.; Fulda, Simone; De Geest, Bruno G.
- 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 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.
- Subjects
NEUROBLASTOMA; GLUTATHIONE peroxidase; CISPLATIN; CANCER cells; NUCLEAR factor of activated T-cells
- Publication
Journal of Clinical Investigation, 2018, Vol 128, Issue 8, p3341
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI99032