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

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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.

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Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis.

Valerian Kagan, Gaowei Mao, Feng Qu … (2017)

Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis-a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls-arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.

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Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway

Vasanthi S Viswanathan, Matthew J. Ryan, Harshil D Dhruv … (2017)

Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial–mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.

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Recent advances in neuroblastoma.

John Maris (2010)

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Author and article information

Contributors

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:

ORCID: http://orcid.org/0000-0001-7163-7728

Guy Van Camp

Dmitri V. Krysko:

ORCID: http://orcid.org/0000-0002-9692-2047

Paul G. Ekert:

ORCID: http://orcid.org/0000-0002-2976-8617

Simone Fulda

Bruno G. De Geest

Marcus Conrad

Valerian E. Kagan

Wim Vanden Berghe:

ORCID: http://orcid.org/0000-0003-0161-7355

Peter Vandenabeele:

ORCID: http://orcid.org/0000-0002-6669-8822

Tom Vanden Berghe:

ORCID: http://orcid.org/0000-0002-1633-0974

Journal

Journal ID (nlm-ta): J Clin Invest

Journal ID (iso-abbrev): J. Clin. Invest

Journal ID (publisher-id): J Clin Invest

Title: The Journal of Clinical Investigation

Publisher: American Society for Clinical Investigation

ISSN (Print): 0021-9738

ISSN (Electronic): 1558-8238

Publication date Created: 25 June 2018

Publication date Created: 1 August 2018

Publication date PMC-release: 1 November 2018

Volume: 128

Issue: 8

Pages: 3341-3355

Affiliations

[1 ]VIB Center for Inflammation Research, Ghent, Belgium.

[2 ]Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.

[3 ]Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Germany.

[4 ]Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

[5 ]Department of Pharmaceutics, Ghent University, Ghent, Belgium.

[6 ]Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.

[7 ]Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.

[8 ]Laboratory of Eukaryotic Gene Expression and Signal Transduction, Department of Physiology, Ghent University, Ghent, Belgium.

[9 ]Laboratory of Protein Chemistry, Proteomics and Epigenetic Signalling (PPES), Department of Biomedical Sciences, University of Antwerp, Wilrijk, Belgium.

[10 ]School of Pharmacy, Pharmaceutical Chemistry, University of Eastern Finland, Kuopio, Finland.

[11 ]Center of Medical Genetics, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.

[12 ]Cancer Research, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia.

[13 ]German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.

[14 ]Methusalem Program, Ghent University, Ghent, Belgium.

Author notes

Address correspondence to: Wim Vanden Berghe, Proteomics and Epigenetic Signalling (PPES), Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium. Phone: 3232652657; Email: Wim.vandenberghe@ 123456uantwerpen.be . Or to: Tom Vanden Berghe or Peter Vandenabeele, VIB Center for Inflammation Research, Ghent, Belgium. Technologiepark 927, 9052 Zwijnaarde, Belgium. Phone: 3293313721; Email: Tom.VandenBerghe@ 123456irc.vib-ugent.be (TVB). Phone: 3293313710; Email: Peter.Vandenabeele@ 123456irc.vib-ugent.be (PV).