2. Academic Validation
  3. A whole-genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors

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

  • EMBO Mol Med. 2023 Feb 6;e16959. doi: 10.15252/emmm.202216959.
Jasmin Taubenschmid-Stowers 1,  Michael Orthofer 2,  Anna Laemmerer 3 4,  Christian Krauditsch 1,  Marianna Rózsová 2,  Christian Studer 5,  Daniela Lötsch 3 6,  Johannes Gojo 4,  Lisa Gabler 3 7 8,  Matheus Dyczynski 2,  Thomas Efferth 9,  Astrid Hagelkruys 1,  Georg Widhalm 6,  Andreas Peyrl 4,  Sabine Spiegl-Kreinecker 10,  Dominic Hoepfner 5,  Shan Bian 1 11 12,  Walter Berger 3,  Juergen A Knoblich 1,  Ulrich Elling 1,  Moritz Horn 2,  Josef M Penninger 1 13
Affiliations

Affiliations

  • 1 IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna Biocenter, Vienna, Austria.
  • 2 JLP Health GmbH, Vienna, Austria.
  • 3 Center for Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumor Unit, Medical University of Vienna, Vienna, Austria.
  • 4 Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.
  • 5 Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • 6 Department of Neurosurgery, Medical University Vienna, Vienna, Austria.
  • 7 Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
  • 8 Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 9 Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany.
  • 10 Department of Neurosurgery, Kepler University Hospital GmbH, Johannes Kepler University Linz, Linz, Austria.
  • 11 Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • 12 Frontier Science Center for Stem Cell Research, Tongji University, Shanghai, China.
  • 13 Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
PMID: 36740985 DOI: 10.15252/emmm.202216959
Abstract

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.

Keywords

5-ALA; Artemisinin; genome wide screen; glioblastoma therapy; porphyrin biogenesis.

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