Nano-targeted double-edged induction of ferroptosis eradicates high-risk neuroblastoma

ABSTRACT: High-risk neuroblastoma is a devastating malignancy with few therapeutic options. We identify withaferin A (WA) as a natural ferroptosis inducing agent in neuroblastoma, which acts through a novel double-edged mechanism. WA targets and inactivates glutathione peroxidase 4, as well as increases intracellular labile Fe(II) upon excessive activation of heme oxygenase-1, which both independently result in ferroptosis. This double-edged mechanism results in a high efficacy of WA compared to etoposide in killing a heterogeneous panel of high-risk neuroblastoma cells, and in suppressing neuroblastoma xenografts growth and relapse rate. Nano-targeting of WA allows systemic application and suppressed tumor growth due to an enhanced targeting to the tumor site. Collectively, our data propose a novel therapeutic strategy to kill cancer cells by ferroptosis. High-risk neuroblastoma is a devastating malignancy with few therapeutic options. We identify withaferin A (WA) as a natural ferroptosis inducing agent in neuroblastoma, which acts through a novel double-edged mechanism. WA targets and inactivates glutathione peroxidase 4, as well as increases intracellular labile Fe(II) upon excessive activation of heme oxygenase-1, which both independently result in ferroptosis. This double-edged mechanism results in a high efficacy of WA compared to etoposide in killing a heterogeneous panel of high-risk neuroblastoma cells, and in suppressing neuroblastoma xenografts growth and relapse rate. Nano-targeting of WA allows systemic application and suppressed tumor growth due to an enhanced targeting to the tumor site. Collectively, our data propose a novel therapeutic strategy to kill cancer cells by ferroptosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE112384 | GEO | 2018/05/01

REPOSITORIES: GEO