Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma
Hassannia B., Wiernicki B., Ingold I., Qu F., Van H. S., Tyurina Y. Y., Bayir H., Abhari B. A., Angeli J. P. F., Choi S. M., Meul E., Heyninck K., Declerck K., Chirumamilla C. S., Lahtela-Kakkonen M., Van C. G., Kry's`ko D. V., Ekert P. G., Fulda S., De G. B. G., Conrad M., Kagan V. E., Berghe W. V., Vandenabeele P., Berghe T. V.
Journal of Clinical Investigation
Vol.128, Issue8, P. 3341-3355
Опубликовано: 2018
Тип ресурса: Статья
Аннотация:
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
Ключевые слова:
cisplatin; etoposide; ferrous ion; heme oxygenase 1; kelch like ECH associated protein 1; phospholipid hydroperoxide glutathione peroxidase; transcription factor Nrf2; withaferin A; heme oxygenase 1; HMOX1 protein, human; kelch like ECH associated protein 1; tumor protein; withaferin A; withanolide; animal cell; animal experiment; animal model; Article; cancer cell; cancer cell line; chorioallantois; CHP-134 cell line; disease eradication; drug efficacy; endothelium cell; ferroptosis; immunoblotting; immunohistochemistry; immunoprecipitation; IMR-32 cell line; Kelly cell line; lipid peroxidation; liquid chromatography-mass spectrometry; lysosome membrane; Michael addition; mouse; NB69 cell line; neuroblastoma; neuroblastoma cell; neuroblastoma cell line; NLF cell line; nonhuman; oncological parameters; oxidative stress; priority journal; residual maximum likelihood; SH-EP cell line; SK-N-DZ cell line; SK-N-SH cell line; therapy effect; therapy resistance; transcriptomics; tumor volume
Язык текста: Английский
ISSN: 1558-8238
Hassannia B.
Wiernicki B.
Ingold I.
Qu F.
Van H. S. Herck S.
Tyurina Y. Y.
Bayir H.
Abhari B. A.
Angeli J. P. F.
Choi S. M.
Meul E.
Heyninck K.
Declerck K.
Chirumamilla C. S.
Lahtela-Kakkonen M.
Van C. G. Camp G.
Kry's`ko D. V. Dmitrij Vadimovich 1975-
Ekert P. G.
Fulda S.
De G. B. G. Geest B.G.
Conrad M.
Kagan V. E. Valerian E 1946-
Berghe W. V.
Vandenabeele P.
Berghe T. V.
Хассанниа Б.
Wиерниcки Б.
Инголд И.
Qу Ф.
Ван Х. С. Херcк С.
Тюрина Y. Y.
Байир Х.
Абхари Б. А.
Ангели Й. П. Ф.
Чои С. М.
Меул Е.
Хеyнинcк К.
Деcлерcк К.
Чирумамилла C. С.
Лахтела-Какконен М.
Ван C. Г. Cамп Г.
Крысько Д. В. Дмитрий Вадимович 1975-
Екерт П. Г.
Фулда С.
Де Г. Б. Г. Геест Б.Г.
Cонрад М.
Каган В. Е. Валериан Е 1946-
Бергхе W. В.
Ванденабееле П.
Бергхе Т. В.
Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma
Текст визуальный непосредственный
Journal of Clinical Investigation
American Society for Clinical Investigation
Vol.128, Issue8 P. 3341-3355
2018
Статья
cisplatin etoposide ferrous ion heme oxygenase 1 kelch like ECH associated protein 1 phospholipid hydroperoxide glutathione peroxidase transcription factor Nrf2 withaferin A heme oxygenase 1 HMOX1 protein, human kelch like ECH associated protein 1 tumor protein withaferin A withanolide animal cell animal experiment animal model Article cancer cell cancer cell line chorioallantois CHP-134 cell line disease eradication drug efficacy endothelium cell ferroptosis immunoblotting immunohistochemistry immunoprecipitation IMR-32 cell line Kelly cell line lipid peroxidation liquid chromatography-mass spectrometry lysosome membrane Michael addition mouse NB69 cell line neuroblastoma neuroblastoma cell neuroblastoma cell line NLF cell line nonhuman oncological parameters oxidative stress priority journal residual maximum likelihood SH-EP cell line SK-N-DZ cell line SK-N-SH cell line therapy effect therapy resistance transcriptomics tumor volume
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