PMID- 37899749 OWN - NLM STAT- MEDLINE DCOM- 20231130 LR - 20231217 IS - 1522-1563 (Electronic) IS - 0363-6143 (Linking) VI - 325 IP - 6 DP - 2023 Dec 1 TI - The iron chelator and OXPHOS inhibitor VLX600 induces mitophagy and an autophagy-dependent type of cell death in glioblastoma cells. PG - C1451-C1469 LID - 10.1152/ajpcell.00293.2023 [doi] AB - Induction of alternative, non-apoptotic cell death programs such as cell-lethal autophagy and mitophagy represent possible strategies 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 U251 ATG5/7 (autophagy related 5/7) knockout (KO) GBM cells and NCH644 ATG5/7 knockdown (KD) glioma stem-like cells (GSCs), suggesting that VLX600 induces an autophagy-dependent cell death (ADCD) in GBM. This ADCD is accompanied by decreased oxygen consumption, increased expression/mitochondrial localization of BNIP3 (BCL2 interacting protein 3) and BNIP3L (BCL2 interacting protein 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, pointing out an important role of iron metabolism for GBM cell homeostasis. Interestingly, VLX600 is also able to completely eliminate NCH644 GSC tumors in an organotypic brain slice transplantation model. Our data support the therapeutic concept of ADCD induction in GBM and suggest that VLX600 may be an interesting novel drug candidate for the treatment of this tumor.NEW & NOTEWORTHY Induction of cell-lethal autophagy represents a possible strategy to combat glioblastoma (GBM). Here, we demonstrate that the novel iron chelator and OXPHOS inhibitor VLX600 exerts pronounced tumor cell-killing effects in adherently cultured GBM cells and glioblastoma stem-like cell (GSC) spheroid cultures that depend on the iron-chelating function of VLX600 and on autophagy activation, underscoring the context-dependent role of autophagy in therapy responses. VLX600 represents an interesting novel drug candidate for the treatment of this tumor. FAU - Reisbeck, Lisa AU - Reisbeck L AD - Experimental Neurosurgery, Department of Neurosurgery, Neuroscience Center, Goethe University Hospital, Frankfurt am Main, Germany. FAU - Linder, Benedikt AU - Linder B AD - Experimental Neurosurgery, Department of Neurosurgery, Neuroscience Center, Goethe University Hospital, Frankfurt am Main, Germany. FAU - Tascher, Georg AU - Tascher G AD - Institute of Biochemistry II, Goethe University, Frankfurt am Main, Germany. FAU - Bozkurt, Suleyman AU - Bozkurt S AD - Institute of Biochemistry II, Goethe University, Frankfurt am Main, Germany. FAU - Weber, Katharina J AU - Weber KJ AD - Neurological Institute (Edinger Institute), Goethe University Hospital, Frankfurt am Main, Germany. AD - Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany. AD - University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany. AD - German Cancer Consortium (DKTK), Partner site Frankfurt/Main, a partnership between DKFZ and University Hospital, Frankfurt, Germany. FAU - Herold-Mende, Christel AU - Herold-Mende C AD - Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany. FAU - van Wijk, Sjoerd J L AU - van Wijk SJL AD - Institute for Pediatric Hematology and Oncology, Goethe University Hospital Frankfurt/Main, Frankfurt am Main, Germany. AD - German Cancer Consortium (DKTK), Partner site Frankfurt/Main, a partnership between DKFZ and University Hospital, Frankfurt, Germany. FAU - Marschalek, Rolf AU - Marschalek R AUID- ORCID: 0000-0003-4870-3445 AD - Institute of Pharmaceutical Biology, Diagnostic Center of Acute Leukemia, University of Frankfurt, Frankfurt/Main, Germany. FAU - Schaefer, Liliana AU - Schaefer L AUID- ORCID: 0000-0002-3318-3005 AD - Institute of Pharmacology and Toxicology, Goethe University, Frankfurt, Germany. FAU - Munch, Christian AU - Munch C AD - Institute of Biochemistry II, Goethe University, Frankfurt am Main, Germany. FAU - Kogel, Donat AU - Kogel D AUID- ORCID: 0000-0003-1209-0210 AD - Experimental Neurosurgery, Department of Neurosurgery, Neuroscience Center, Goethe University Hospital, Frankfurt am Main, Germany. AD - German Cancer Consortium (DKTK), Partner site Frankfurt/Main, a partnership between DKFZ and University Hospital, Frankfurt, Germany. LA - eng GR - 259130777/Deutsche Forschungsgemeinschaft (DFG)/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20231030 PL - United States TA - Am J Physiol Cell Physiol JT - American journal of physiology. Cell physiology JID - 100901225 RN - 0 (VLX600) RN - 0 (Antineoplastic Agents) RN - 0 (Mitochondrial Proteins) RN - 0 (Iron Chelating Agents) RN - E1UOL152H7 (Iron) RN - 0 (Proto-Oncogene Proteins c-bcl-2) SB - IM MH - Humans MH - Mitophagy/physiology MH - *Glioblastoma/drug therapy/genetics/pathology MH - Autophagy MH - *Antineoplastic Agents/pharmacology MH - Apoptosis MH - Mitochondrial Proteins/metabolism MH - Iron Chelating Agents/pharmacology MH - Iron MH - Proto-Oncogene Proteins c-bcl-2 MH - Cell Line, Tumor OTO - NOTNLM OT - autophagy OT - brain tumor OT - iron metabolism OT - mitophagy OT - non-apoptotic cell death EDAT- 2023/10/30 06:47 MHDA- 2023/11/30 06:43 CRDT- 2023/10/30 04:23 PHST- 2023/11/30 06:43 [medline] PHST- 2023/10/30 06:47 [pubmed] PHST- 2023/10/30 04:23 [entrez] AID - 10.1152/ajpcell.00293.2023 [doi] PST - ppublish SO - Am J Physiol Cell Physiol. 2023 Dec 1;325(6):C1451-C1469. doi: 10.1152/ajpcell.00293.2023. Epub 2023 Oct 30.