A whole‐genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors

The natural compound Artemisinin is the most widely used antimalarial drug worldwide. Based on its cytotoxicity, it is also used for anticancer therapy. Artemisinin and its derivates are endoperoxides that damage proteins in eukaryotic cells; their definite mechanism of action and host cell targets,...

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Veröffentlicht in:EMBO molecular medicine Jg. 15; H. 3; S. e16959 - n/a
Hauptverfasser: Taubenschmid‐Stowers, Jasmin, Orthofer, Michael, Laemmerer, Anna, Krauditsch, Christian, Rózsová, Marianna, Studer, Christian, Lötsch, Daniela, Gojo, Johannes, Gabler, Lisa, Dyczynski, Matheus, Efferth, Thomas, Hagelkruys, Astrid, Widhalm, Georg, Peyrl, Andreas, Spiegl‐Kreinecker, Sabine, Hoepfner, Dominic, Bian, Shan, Berger, Walter, Knoblich, Juergen A, Elling, Ulrich, Horn, Moritz, Penninger, Josef M
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 08.03.2023
EMBO Press
John Wiley and Sons Inc
Springer Nature
Schlagworte:
5‐ALA
Aminolevulinic Acid
Antimalarials - pharmacology
Artemisinin
Artemisinins - pharmacology
Artemisinins - therapeutic use
Biosynthesis
Brain cancer
Brain Neoplasms - drug therapy
Brain tumors
Breast cancer
Carbon
Cytotoxicity
Dihydroartemisinin
Drug resistance
EMBO03
EMBO08
Genetic engineering
genome wide screen
Genomes
Glioblastoma
glioblastoma therapy
Glycerol
Heme
Heme - metabolism
Humans
Malaria
Mutagenesis
Organoids
porphyrin biogenesis
Porphyrins
Proteins
Spheroids
Stem cells
Tumor cells
Tumors
Xenografts
Yeast
genome wide screen
porphyrin biogenesis
5‐ALA
glioblastoma therapy
Artemisinin
5-ALA
ISSN:1757-4676, 1757-4684, 1757-4684
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Zusammenfassung:The natural compound Artemisinin is the most widely used antimalarial drug worldwide. Based on its cytotoxicity, it is also used for anticancer therapy. Artemisinin and its derivates are endoperoxides that damage proteins in eukaryotic cells; their definite mechanism of action and host cell targets, however, have remained largely elusive. Using yeast and haploid stem cell screening, we demonstrate that a single cellular pathway, namely porphyrin (heme) biosynthesis, is required for the cytotoxicity of Artemisinins. Genetic or pharmacological modulation of porphyrin production is sufficient to alter its cytotoxicity in eukaryotic cells. Using multiple model systems of human brain tumor development, such as cerebral glioblastoma organoids, and patient‐derived tumor spheroids, we sensitize cancer cells to dihydroartemisinin using the clinically approved porphyrin enhancer and surgical fluorescence marker 5‐aminolevulinic acid, 5‐ALA. A combination treatment of Artemisinins and 5‐ALA markedly and specifically killed brain tumor cells in all model systems tested, including orthotopic patient‐derived xenografts in vivo . These data uncover the critical molecular pathway for Artemisinin cytotoxicity and a sensitization strategy to treat different brain tumors, including drug‐resistant human glioblastomas. Synopsis Artemisinin requires cellular heme for its cytotoxic function. Its cytotoxicity can be increased by the porphyrin enhancer 5‐ALA, which accumulates in cancer cells. 5‐ALA sensitizes tumor cell. Haploid yeast and mouse ESC genetic screens identify porphyrin production as essential for Artemisinin's cytotoxicity. Ablation of mitochondrial heme/porphyrin biosynthesis increases resistance of cells to Artemisinin derivatives; elevating heme production leads to sensitization. The metabolite 5‐ALA induces porphyrin synthesis and thereby sensitizes cancer cells to Artemisinin killing. Graphical Abstract Artemisinin requires cellular heme for its cytotoxic function. Its cytotoxicity can be increased by the porphyrin enhancer 5‐ALA, which accumulates in cancer cells. 5‐ALA sensitizes tumor cell.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:1757-4676
1757-4684
1757-4684
DOI:10.15252/emmm.202216959