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

(2018) JOURNAL OF CLINICAL INVESTIGATION. 128(8). p.3341-3355
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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.
Keywords
CELL-DEATH, CANCER-CELLS, OXIDATIVE STRESS, WITHANIA-SOMNIFERA, TUMOR-GROWTH, IRON, THERAPY, PATHWAY, EXPRESSION, GPX4

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Chicago
Hassannia, Behrouz, Bartosz Wiernicki, Irina Ingold, Feng Qu, Simon Van Herck, Yulia Y. Tyurina, Hülya Bayır, et al. 2018. “Nano-targeted Induction of Dual Ferroptotic Mechanisms Eradicates High-risk Neuroblastoma.” Journal of Clinical Investigation 128 (8): 3341–3355.
APA
Hassannia, B., Wiernicki, B., Ingold, I., Qu, F., Van Herck, S., Tyurina, Y. Y., Bayır, H., et al. (2018). Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. JOURNAL OF CLINICAL INVESTIGATION, 128(8), 3341–3355.
Vancouver
1.
Hassannia B, Wiernicki B, Ingold I, Qu F, Van Herck S, Tyurina YY, et al. Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. JOURNAL OF CLINICAL INVESTIGATION. 2018;128(8):3341–55.
MLA
Hassannia, Behrouz, Bartosz Wiernicki, Irina Ingold, et al. “Nano-targeted Induction of Dual Ferroptotic Mechanisms Eradicates High-risk Neuroblastoma.” JOURNAL OF CLINICAL INVESTIGATION 128.8 (2018): 3341–3355. Print.
@article{8575148,
  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.},
  author       = {Hassannia, Behrouz and Wiernicki, Bartosz and Ingold, Irina and Qu, Feng and Van Herck, Simon and Tyurina, Yulia Y. and Bay{\i}r, H{\"u}lya and Abhari, Behnaz A. and Angeli, Jose Pedro Friedmann and Choi, Sze Men and Meul, Eline and Heyninck, Karen and Declerck, Ken and Chirumamilla, Chandra Sekhar and Lahtela-Kakkonen, Maija and Van Camp, Guy and Krysko, Dmitri and Ekert, Paul G. and Fulda, Simone and De Geest, Bruno and Conrad, Marcus and Kagan, Valerian and Vanden Berghe, Wim and Vandenabeele, Peter and Vanden Berghe, Tom},
  issn         = {0021-9738},
  journal      = {JOURNAL OF CLINICAL INVESTIGATION},
  language     = {eng},
  number       = {8},
  pages        = {3341--3355},
  title        = {Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma},
  url          = {http://dx.doi.org/10.1172/jci99032},
  volume       = {128},
  year         = {2018},
}

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