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The iron chelator and OXPHOS inhibitor VLX600 induces mitophagy and an autophagy-dependent type of cell death in glioblastoma cells

Induction of alternative, non-apoptotic cell death programs such as cell-lethal autophagy and mitophagy represent possible strat-egies to combat glioblastoma (GBM). Here we report that VLX600, a novel iron chelator and oxidative phosphorylation(OXPHOS) inhibitor, induces a caspase-in...

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Main Authors: Reisbeck, Lisa (Author) , Linder, Benedikt (Author) , Tascher, Georg (Author) , Bozkurt, Süleyman (Author) , Weber, Katharina J. (Author) , Herold-Mende, Christel (Author) , van Wijk, Sjoerd J. L. (Author) , Marschalek, Rolf (Author) , Schaefer, Liliana (Author) , Münch, Christian (Author) , Kögel, Donat (Author)
Format: Article (Journal)
Language:English
Published: December 2023
In: American journal of physiology. Cell physiology
Year: 2023, Volume: 325, Issue: 6, Pages: C1451-C1469
ISSN:1522-1563
DOI:10.1152/ajpcell.00293.2023
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1152/ajpcell.00293.2023
Verlag, lizenzpflichtig, Volltext: https://journals.physiology.org/doi/full/10.1152/ajpcell.00293.2023
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Author Notes:Lisa Reisbeck, Benedikt Linder, Georg Tascher, Süleyman Bozkurt, Katharina J. Weber, Christel Herold-Mende, Sjoerd J.L. van Wijk, Rolf Marschalek, Liliana Schaefer, Christian Münch, and Donat Kögel
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Summary:Induction of alternative, non-apoptotic cell death programs such as cell-lethal autophagy and mitophagy represent possible strat-egies to combat glioblastoma (GBM). Here we report that VLX600, a novel iron chelator and oxidative phosphorylation(OXPHOS) inhibitor, induces a caspase-independent type of cell death that is partially rescued in adherent U251ATG5/7(autoph-agy related 5/7) knockout (KO) GBM cells and NCH644ATG5/7knockdown (KD) glioma stem-like cells (GSCs), suggesting thatVLX600 induces an autophagy-dependent cell death (ADCD) in GBM. This ADCD is accompanied by decreased oxygen con-sumption, increased expression/mitochondrial localization of BNIP3 (BCL2 interacting protein 3) and BNIP3L (BCL2 interactingprotein 3 like), the induction of mitophagy as demonstrated by diminished levels of mitochondrial marker proteins [e.g., COX4I1(cytochrome c oxidase subunit 4I1)] and the mitoKeima assay as well as increased histone H3 and H4 lysine tri-methylation.Furthermore, the extracellular addition of iron is able to significantly rescue VLX600-induced cell death and mitophagy, pointingout an important role of iron metabolism for GBM cell homeostasis. Interestingly, VLX600 is also able to completely eliminateNCH644 GSC tumors in an organotypic brain slice transplantation model. Our data support the therapeutic concept of ADCDinduction in GBM and suggest that VLX600 may be an interesting novel drug candidate for the treatment of this tumor.
Item Description:Online veröffentlicht: 30. Oktober 2023
Gesehen am 10.05.2024
Physical Description:Online Resource
ISSN:1522-1563
DOI:10.1152/ajpcell.00293.2023

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