Taubenschmid-Stowers, Jasmin, Krauditsch, Christian, Studer, Christian, Lämmerer, Anna, Lötsch, Daniela, Gojo, Johannes, Widhalm, Georg, Peyrl, Andreas, Spiegl-Kreinecker, Sabine, Berger, Walter, Hoepfner, Dominic, Bian, Shan, Knoblich, Juergen, Elling, Ulrich and Penninger, Josef M. (2022) A whole genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain cancer. EMBO molecular medicine, e16959 (e16959). pp. 1-20. ISSN 1757-4684; 1757-4676

Abstract

The natural medical compound Artemisinin is the most widely used anti-malarial drug worldwide. Based on its cytotoxic activity, it is also being used for anti-cancer therapy. Artemisinin is an endoperoxide that damages proteins in eukaryotic cells; its definite mechanism of action and critical host cell targets, however, have remained largely elusive. Using hip-hop yeast profiling and haploid ES cell screening, we demonstrate that only a single cellular pathway, namely (mitochondrial) porphyrin or heme biosynthesis, is accountable for Artemisinin’s cytotoxicity. Genetic or pharmacological modulation of porphyrin production is sufficient to alter the cytotoxic activity of Artemisinin in multiple eukaryotic cells, including human cancer cells. Using multiple clinically relevant model systems of human brain tumor development, such as glioblastomas in engineered cerebral organoids and patient-derived brain tumor spheroids, we translated our screen to sensitize brain cancer cells to Artemisinin using the metabolite 5-ALA, a photodynamic porphyrin enhancer. A combination treatment with Artemisinin and 5-ALA markedly killed brain tumor cells in all model systems tested, including in multidrug resistance cancers. These data uncover the critical molecular pathway for Artemisinin cytotoxicity and a sensitization strategy to treat multiple brain tumors, including largely untreatable human glioblastomas.

Item Type:	Article
Keywords:	Artemisinin, 5-ALA, Glioblastoma, PPOX, Mechanism of Action
Date Deposited:	14 Mar 2023 00:45
Last Modified:	14 Mar 2023 00:45
URI:	https://oak.novartis.com/id/eprint/42657