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

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

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.

Authors

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

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Figure 5

Nano-targeting of WA avoids systemic side effects and suppresses tumor growth.

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Nano-targeting of WA avoids systemic side effects and suppresses tumor g...
(A) Schematic representation of the amphiphilic degradable pH-sensitive nanoparticle encapsulating WA (WA-NP). (B) Histogram indicating the size of empty (Empty-NP) and WA-encapsulated nanoparticles (WA-NP). d;nm means diameter of nanoparticles in nanometer. (C) Percentage of cell death in function of time triggered by WA-NPs, Empty-NPs, and WA in IMR-32 cells. (D) Percentage of body weight change in mice 4 days after daily i.p. injection of WA and vehicle. (E) In vivo fluorescence images of neuroblastoma tumor xenografts in nude mice injected i.p. with Cy5 and Cy5-loaded nanoparticles (Cy5-NPs). (F) Percentage of body weight change in mice 9 days after daily i.p. injection of empty (Empty-NP) or WA-encapsulated nanoparticles (WA-NP). (G) Quantification of tumor growth rates after therapeutic treatment regime (60–70 mm3 at the start of injection) with empty (Empty-NP) or WA-encapsulated nanoparticles (WA-NP). Each point indicates an individual mouse. Error bars represents SEM; n = 8 per group. (H) PL•, phospholipid radical; PLOO•, phospholipid peroxyradical; LOOH, phospholipid hydroperoxide; PLOH, phospholipid alcohol. Schematic representation of a double-edged ferroptosis induction mechanism upon WA exposure. WA induces uncontrolled lipid peroxidation and ferroptosis through inactivation of GPX4 (canonical ferroptosis induction) and excessive activation of HMOX1 followed by an increase in the labile Fe(II) pool (noncanonical ferroptosis induction). Inhibiting the lipid detoxification process, by inactivating GPX4, as well as fueling the reactive free radical chain process by increasing the labile Fe(II) pool effectively boosts ferroptosis. *P < 0.05; **P < 0.001, 2-tailed t test (D and G).