Journal Article

Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma

Bayır, Hülya, Chirumamilla, Chandra Sekhar, Ekert, Paul G., Krysko, Dmitri V., Abhari, Behnaz A., Van Herck, Simon, Qu, Feng, Kagan, Valerian E., Meul, Eline, Hassannia, Behrouz, Wiernicki, Bartosz, Conrad, Marcus, Fulda, Simone, Lahtela-Kakkonen, Maija, Declerck, Ken, Vanden Berghe, Tom, Angeli, Jose Pedro Friedmann, Ingold, Irina, Heyninck, Karen, Tyurina, Yulia Y., Vandenabeele, Peter, Van Camp, Guy, De Geest, Bruno G., Choi, Sze Men, Vanden Berghe, Wim

2018

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Analysis / Angiogenesis / Animals / Apoptosis / Apoptosis - drug effects / Biomedical research / Cancer / Cancer cells / Cancer therapies / Care and treatment / Cell Line, Tumor / Chick Embryo / Cisplatin / Cysts / Cytology / Data processing / Dosage and administration / Enzymes / Etoposide / Ferroptosis / Gangrene / Gene expression / Glutathione peroxidase / Heme / Heme oxygenase (decyclizing) / Heme Oxygenase-1 - metabolism / Humans / Iron / Kelch-Like ECH-Associated Protein 1 - metabolism / Kinases / Lipid peroxidation / Lipids / Malignancy / Mice / Morphology / Nanoparticles / Neoplasm Proteins - metabolism / Neuroblastoma / Neuroblastoma - drug therapy / Neuroblastoma - metabolism / Neuroblastoma - pathology / Neuroblasts / Oxygenase / Prognosis / Proteins / Risk factors / Steroids (Drugs) / Withanolides - pharmacology / Xenograft Model Antitumor Assays / Xenografts