Journal
EMBO MOLECULAR MEDICINE
Volume 15, Issue 3, Pages -Publisher
WILEY
DOI: 10.15252/emmm.202216959
Keywords
5-ALA; Artemisinin; genome wide screen; glioblastoma therapy; porphyrin biogenesis
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The natural compound Artemisinin is widely used as an antimalarial drug and has potential for anticancer therapy. Through screening with yeast and haploid stem cells, it has been discovered that the porphyrin biosynthesis pathway is crucial for the cytotoxicity of Artemisinin. In various human brain tumor models, a combination treatment of Artemisinin and the porphyrin enhancer 5-aminolevulinic acid sensitizes and kills brain tumor cells.
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.
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