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

Abstract

AbstractThe 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.

Autoren

Jasmin Taubenschmid‐Stowers
Michael Orthofer
Anna Laemmerer
Christian Krauditsch
Marianna Rózsová
Christian Studer
Daniela Lötsch
Johannes Gojo
Lisa Gabler
Matheus Dyczynski
Thomas Efferth
Astrid Hagelkruys
Georg Widhalm
Andreas Peyrl
Sabine Spiegl‐Kreinecker
Dominic Hoepfner
Shan Bian
Walter Berger
Juergen A Knoblich
Ulrich Elling
Moritz Horn
Josef M Penninger

DOI

10.15252/emmm.202216959

eISSN

1757-4684

ISSN

1757-4676

Ausgabe der Veröffentlichung

3

Zeitschrift

EMBO Molecular Medicine

Sprache

en

Online publication date

2023

Datum der Veröffentlichung

2023

Status

Published

Herausgeber

Springer Science and Business Media LLC

Herausgeber URL

http://dx.doi.org/10.15252/emmm.202216959

Datum der Datenerfassung

2023

Titel

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

Ausgabe der Zeitschrift

15

Data source: Crossref

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.

Addresses

IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna Biocenter, Vienna, Austria.

Autoren

Jasmin Taubenschmid-Stowers
Michael Orthofer
Anna Laemmerer
Christian Krauditsch
Marianna Rózsová
Christian Studer
Daniela Lötsch
Johannes Gojo
Lisa Gabler
Matheus Dyczynski
Thomas Efferth
Astrid Hagelkruys
Georg Widhalm
Andreas Peyrl
Sabine Spiegl-Kreinecker
Dominic Hoepfner
Shan Bian
Walter Berger
Juergen A Knoblich
Ulrich Elling
Moritz Horn
Josef M Penninger

DOI

10.15252/emmm.202216959

eISSN

1757-4684

Externe Identifier

PubMed Identifier: 36740985
PubMed Central ID: PMC10237280

Funding acknowledgements

Austrian Science Fund FWF: Z 271
Austrian Science Fund FWF: P 30105
European Research Council: 341036
European Research Council: 695642
Canada Research Chairs: F18‐01336
Austrian Science Fund FWF: I 4164
Austrian Science Fund FWF: P30105
Austrian Science Fund FWF: Z 271‐B19
Österreichische Forschungsförderungsgesellschaft: 879800

Open access

true

ISSN

1757-4676

Ausgabe der Veröffentlichung

3

Zeitschrift

EMBO molecular medicine

Schlüsselwörter

Humans
Brain Neoplasms
Aminolevulinic Acid
Artemisinins
Heme
Antimalarials

Sprache

eng

Medium

Print-Electronic

Online publication date

2023

Open access status

Open Access

Paginierung

e16959

Datum der Veröffentlichung

2023

Status

Published

Publisher licence

CC BY

Datum der Datenerfassung

2023

Titel

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

Sub types

Research Support, Non-U.S. Gov't
research-article
Journal Article

Ausgabe der Zeitschrift

15

Files

https://europepmc.org/articles/PMC10237280?pdf=render

Data source: Europe PubMed Central

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.

Date of acceptance

2022

Autoren

Jasmin Taubenschmid-Stowers
Michael Orthofer
Anna Laemmerer
Christian Krauditsch
Marianna Rózsová
Christian Studer
Daniela Lötsch
Johannes Gojo
Lisa Gabler
Matheus Dyczynski
Thomas Efferth
Astrid Hagelkruys
Georg Widhalm
Andreas Peyrl
Sabine Spiegl-Kreinecker
Dominic Hoepfner
Shan Bian
Walter Berger
Juergen A Knoblich
Ulrich Elling
Moritz Horn
Josef M Penninger

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/36740985

DOI

10.15252/emmm.202216959

eISSN

1757-4684

Externe Identifier

PubMed Central ID: PMC10237280

Funding acknowledgements

Austrian Science Fund FWF: P 30105

Ausgabe der Veröffentlichung

3

Zeitschrift

EMBO Mol Med

Schlüsselwörter

5-ALA
Artemisinin
genome wide screen
glioblastoma therapy
porphyrin biogenesis
Humans
Artemisinins
Antimalarials
Heme
Aminolevulinic Acid
Brain Neoplasms

Sprache

eng

Country

England

Paginierung

e16959

Datum der Veröffentlichung

2023

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2023

Titel

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

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

15

Data source: PubMed

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

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