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

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

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	5‐ALA Artemisinin genome wide screen glioblastoma therapy porphyrin biogenesis

Übergeordnetes Werk:	In: EMBO Molecular Medicine - Wiley, 2012, 15(2023), 3, Seite n/a-n/a
Übergeordnetes Werk:	volume:15 ; year:2023 ; number:3 ; pages:n/a-n/a

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.15252/emmm.202216959

Katalog-ID:	DOAJ088190536

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520			\|a 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.
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700	0		\|a Marianna Rózsová \|e verfasserin \|4 aut
700	0		\|a Christian Studer \|e verfasserin \|4 aut
700	0		\|a Daniela Lötsch \|e verfasserin \|4 aut
700	0		\|a Johannes Gojo \|e verfasserin \|4 aut
700	0		\|a Lisa Gabler \|e verfasserin \|4 aut
700	0		\|a Matheus Dyczynski \|e verfasserin \|4 aut
700	0		\|a Thomas Efferth \|e verfasserin \|4 aut
700	0		\|a Astrid Hagelkruys \|e verfasserin \|4 aut
700	0		\|a Georg Widhalm \|e verfasserin \|4 aut
700	0		\|a Andreas Peyrl \|e verfasserin \|4 aut
700	0		\|a Sabine Spiegl‐Kreinecker \|e verfasserin \|4 aut
700	0		\|a Dominic Hoepfner \|e verfasserin \|4 aut
700	0		\|a Shan Bian \|e verfasserin \|4 aut
700	0		\|a Walter Berger \|e verfasserin \|4 aut
700	0		\|a Juergen A Knoblich \|e verfasserin \|4 aut
700	0		\|a Ulrich Elling \|e verfasserin \|4 aut
700	0		\|a Moritz Horn \|e verfasserin \|4 aut
700	0		\|a Josef M Penninger \|e verfasserin \|4 aut
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allfields	10.15252/emmm.202216959 doi (DE-627)DOAJ088190536 (DE-599)DOAJ7735106cb6194b64bd51f140f2fd01c5 DE-627 ger DE-627 rakwb eng R5-920 QH426-470 Jasmin Taubenschmid‐Stowers verfasserin aut A whole‐genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. 5‐ALA Artemisinin genome wide screen glioblastoma therapy porphyrin biogenesis Medicine (General) Genetics Michael Orthofer verfasserin aut Anna Laemmerer verfasserin aut Christian Krauditsch verfasserin aut Marianna Rózsová verfasserin aut Christian Studer verfasserin aut Daniela Lötsch verfasserin aut Johannes Gojo verfasserin aut Lisa Gabler verfasserin aut Matheus Dyczynski verfasserin aut Thomas Efferth verfasserin aut Astrid Hagelkruys verfasserin aut Georg Widhalm verfasserin aut Andreas Peyrl verfasserin aut Sabine Spiegl‐Kreinecker verfasserin aut Dominic Hoepfner verfasserin aut Shan Bian verfasserin aut Walter Berger verfasserin aut Juergen A Knoblich verfasserin aut Ulrich Elling verfasserin aut Moritz Horn verfasserin aut Josef M Penninger verfasserin aut In EMBO Molecular Medicine Wiley, 2012 15(2023), 3, Seite n/a-n/a (DE-627)594772761 (DE-600)2485479-7 17574684 nnns volume:15 year:2023 number:3 pages:n/a-n/a https://doi.org/10.15252/emmm.202216959 kostenfrei https://doaj.org/article/7735106cb6194b64bd51f140f2fd01c5 kostenfrei https://doi.org/10.15252/emmm.202216959 kostenfrei https://doaj.org/toc/1757-4676 Journal toc kostenfrei https://doaj.org/toc/1757-4684 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2023 3 n/a-n/a
spelling	10.15252/emmm.202216959 doi (DE-627)DOAJ088190536 (DE-599)DOAJ7735106cb6194b64bd51f140f2fd01c5 DE-627 ger DE-627 rakwb eng R5-920 QH426-470 Jasmin Taubenschmid‐Stowers verfasserin aut A whole‐genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. 5‐ALA Artemisinin genome wide screen glioblastoma therapy porphyrin biogenesis Medicine (General) Genetics Michael Orthofer verfasserin aut Anna Laemmerer verfasserin aut Christian Krauditsch verfasserin aut Marianna Rózsová verfasserin aut Christian Studer verfasserin aut Daniela Lötsch verfasserin aut Johannes Gojo verfasserin aut Lisa Gabler verfasserin aut Matheus Dyczynski verfasserin aut Thomas Efferth verfasserin aut Astrid Hagelkruys verfasserin aut Georg Widhalm verfasserin aut Andreas Peyrl verfasserin aut Sabine Spiegl‐Kreinecker verfasserin aut Dominic Hoepfner verfasserin aut Shan Bian verfasserin aut Walter Berger verfasserin aut Juergen A Knoblich verfasserin aut Ulrich Elling verfasserin aut Moritz Horn verfasserin aut Josef M Penninger verfasserin aut In EMBO Molecular Medicine Wiley, 2012 15(2023), 3, Seite n/a-n/a (DE-627)594772761 (DE-600)2485479-7 17574684 nnns volume:15 year:2023 number:3 pages:n/a-n/a https://doi.org/10.15252/emmm.202216959 kostenfrei https://doaj.org/article/7735106cb6194b64bd51f140f2fd01c5 kostenfrei https://doi.org/10.15252/emmm.202216959 kostenfrei https://doaj.org/toc/1757-4676 Journal toc kostenfrei https://doaj.org/toc/1757-4684 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2023 3 n/a-n/a
allfields_unstemmed	10.15252/emmm.202216959 doi (DE-627)DOAJ088190536 (DE-599)DOAJ7735106cb6194b64bd51f140f2fd01c5 DE-627 ger DE-627 rakwb eng R5-920 QH426-470 Jasmin Taubenschmid‐Stowers verfasserin aut A whole‐genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. 5‐ALA Artemisinin genome wide screen glioblastoma therapy porphyrin biogenesis Medicine (General) Genetics Michael Orthofer verfasserin aut Anna Laemmerer verfasserin aut Christian Krauditsch verfasserin aut Marianna Rózsová verfasserin aut Christian Studer verfasserin aut Daniela Lötsch verfasserin aut Johannes Gojo verfasserin aut Lisa Gabler verfasserin aut Matheus Dyczynski verfasserin aut Thomas Efferth verfasserin aut Astrid Hagelkruys verfasserin aut Georg Widhalm verfasserin aut Andreas Peyrl verfasserin aut Sabine Spiegl‐Kreinecker verfasserin aut Dominic Hoepfner verfasserin aut Shan Bian verfasserin aut Walter Berger verfasserin aut Juergen A Knoblich verfasserin aut Ulrich Elling verfasserin aut Moritz Horn verfasserin aut Josef M Penninger verfasserin aut In EMBO Molecular Medicine Wiley, 2012 15(2023), 3, Seite n/a-n/a (DE-627)594772761 (DE-600)2485479-7 17574684 nnns volume:15 year:2023 number:3 pages:n/a-n/a https://doi.org/10.15252/emmm.202216959 kostenfrei https://doaj.org/article/7735106cb6194b64bd51f140f2fd01c5 kostenfrei https://doi.org/10.15252/emmm.202216959 kostenfrei https://doaj.org/toc/1757-4676 Journal toc kostenfrei https://doaj.org/toc/1757-4684 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2023 3 n/a-n/a
allfieldsGer	10.15252/emmm.202216959 doi (DE-627)DOAJ088190536 (DE-599)DOAJ7735106cb6194b64bd51f140f2fd01c5 DE-627 ger DE-627 rakwb eng R5-920 QH426-470 Jasmin Taubenschmid‐Stowers verfasserin aut A whole‐genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. 5‐ALA Artemisinin genome wide screen glioblastoma therapy porphyrin biogenesis Medicine (General) Genetics Michael Orthofer verfasserin aut Anna Laemmerer verfasserin aut Christian Krauditsch verfasserin aut Marianna Rózsová verfasserin aut Christian Studer verfasserin aut Daniela Lötsch verfasserin aut Johannes Gojo verfasserin aut Lisa Gabler verfasserin aut Matheus Dyczynski verfasserin aut Thomas Efferth verfasserin aut Astrid Hagelkruys verfasserin aut Georg Widhalm verfasserin aut Andreas Peyrl verfasserin aut Sabine Spiegl‐Kreinecker verfasserin aut Dominic Hoepfner verfasserin aut Shan Bian verfasserin aut Walter Berger verfasserin aut Juergen A Knoblich verfasserin aut Ulrich Elling verfasserin aut Moritz Horn verfasserin aut Josef M Penninger verfasserin aut In EMBO Molecular Medicine Wiley, 2012 15(2023), 3, Seite n/a-n/a (DE-627)594772761 (DE-600)2485479-7 17574684 nnns volume:15 year:2023 number:3 pages:n/a-n/a https://doi.org/10.15252/emmm.202216959 kostenfrei https://doaj.org/article/7735106cb6194b64bd51f140f2fd01c5 kostenfrei https://doi.org/10.15252/emmm.202216959 kostenfrei https://doaj.org/toc/1757-4676 Journal toc kostenfrei https://doaj.org/toc/1757-4684 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2023 3 n/a-n/a
allfieldsSound	10.15252/emmm.202216959 doi (DE-627)DOAJ088190536 (DE-599)DOAJ7735106cb6194b64bd51f140f2fd01c5 DE-627 ger DE-627 rakwb eng R5-920 QH426-470 Jasmin Taubenschmid‐Stowers verfasserin aut A whole‐genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. 5‐ALA Artemisinin genome wide screen glioblastoma therapy porphyrin biogenesis Medicine (General) Genetics Michael Orthofer verfasserin aut Anna Laemmerer verfasserin aut Christian Krauditsch verfasserin aut Marianna Rózsová verfasserin aut Christian Studer verfasserin aut Daniela Lötsch verfasserin aut Johannes Gojo verfasserin aut Lisa Gabler verfasserin aut Matheus Dyczynski verfasserin aut Thomas Efferth verfasserin aut Astrid Hagelkruys verfasserin aut Georg Widhalm verfasserin aut Andreas Peyrl verfasserin aut Sabine Spiegl‐Kreinecker verfasserin aut Dominic Hoepfner verfasserin aut Shan Bian verfasserin aut Walter Berger verfasserin aut Juergen A Knoblich verfasserin aut Ulrich Elling verfasserin aut Moritz Horn verfasserin aut Josef M Penninger verfasserin aut In EMBO Molecular Medicine Wiley, 2012 15(2023), 3, Seite n/a-n/a (DE-627)594772761 (DE-600)2485479-7 17574684 nnns volume:15 year:2023 number:3 pages:n/a-n/a https://doi.org/10.15252/emmm.202216959 kostenfrei https://doaj.org/article/7735106cb6194b64bd51f140f2fd01c5 kostenfrei https://doi.org/10.15252/emmm.202216959 kostenfrei https://doaj.org/toc/1757-4676 Journal toc kostenfrei https://doaj.org/toc/1757-4684 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2023 3 n/a-n/a
language	English
source	In EMBO Molecular Medicine 15(2023), 3, Seite n/a-n/a volume:15 year:2023 number:3 pages:n/a-n/a
sourceStr	In EMBO Molecular Medicine 15(2023), 3, Seite n/a-n/a volume:15 year:2023 number:3 pages:n/a-n/a
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	5‐ALA Artemisinin genome wide screen glioblastoma therapy porphyrin biogenesis Medicine (General) Genetics
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container_title	EMBO Molecular Medicine
authorswithroles_txt_mv	Jasmin Taubenschmid‐Stowers @@aut@@ Michael Orthofer @@aut@@ Anna Laemmerer @@aut@@ Christian Krauditsch @@aut@@ Marianna Rózsová @@aut@@ Christian Studer @@aut@@ Daniela Lötsch @@aut@@ Johannes Gojo @@aut@@ Lisa Gabler @@aut@@ Matheus Dyczynski @@aut@@ Thomas Efferth @@aut@@ Astrid Hagelkruys @@aut@@ Georg Widhalm @@aut@@ Andreas Peyrl @@aut@@ Sabine Spiegl‐Kreinecker @@aut@@ Dominic Hoepfner @@aut@@ Shan Bian @@aut@@ Walter Berger @@aut@@ Juergen A Knoblich @@aut@@ Ulrich Elling @@aut@@ Moritz Horn @@aut@@ Josef M Penninger @@aut@@
publishDateDaySort_date	2023-01-01T00:00:00Z
hierarchy_top_id	594772761
id	DOAJ088190536
language_de	englisch
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callnumber-first	R - Medicine
author	Jasmin Taubenschmid‐Stowers
spellingShingle	Jasmin Taubenschmid‐Stowers misc R5-920 misc QH426-470 misc 5‐ALA misc Artemisinin misc genome wide screen misc glioblastoma therapy misc porphyrin biogenesis misc Medicine (General) misc Genetics A whole‐genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors
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topic_title	R5-920 QH426-470 A whole‐genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors 5‐ALA Artemisinin genome wide screen glioblastoma therapy porphyrin biogenesis
topic	misc R5-920 misc QH426-470 misc 5‐ALA misc Artemisinin misc genome wide screen misc glioblastoma therapy misc porphyrin biogenesis misc Medicine (General) misc Genetics
topic_unstemmed	misc R5-920 misc QH426-470 misc 5‐ALA misc Artemisinin misc genome wide screen misc glioblastoma therapy misc porphyrin biogenesis misc Medicine (General) misc Genetics
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title	A whole‐genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors
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title_full	A whole‐genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors
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title_sort	whole‐genome scan for artemisinin cytotoxicity reveals a novel therapy for human brain tumors
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title_auth	A whole‐genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors
abstract	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.
abstractGer	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.
abstract_unstemmed	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.
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container_issue	3
title_short	A whole‐genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors
url	https://doi.org/10.15252/emmm.202216959 https://doaj.org/article/7735106cb6194b64bd51f140f2fd01c5 https://doaj.org/toc/1757-4676 https://doaj.org/toc/1757-4684
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author2	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
author2Str	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
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doi_str	10.15252/emmm.202216959
callnumber-a	R5-920
up_date	2024-07-03T16:20:25.138Z
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