Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells

Glioblastoma represents the highest grade of brain tumors. Despite maximal resection surgery associated with radiotherapy and concomitant followed by adjuvant chemotherapy with temozolomide (TMZ), patients have a very poor prognosis due to the rapid recurrence and the acquisition of resistance to TM...

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Autores principales:	Luca X. Zampieri, Martina Sboarina, Andrea Cacace, Debora Grasso, Léopold Thabault, Loïc Hamelin, Thibaut Vazeille, Elodie Dumon, Rodrigue Rossignol, Raphaël Frédérick, Etienne Sonveaux, Florence Lefranc, Pierre Sonveaux
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	glioblastoma chemoresistance temozolomide (TMZ) cancer metabolism mitochondria PARP inhibitors Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/666aff1d5374431b9cb3e655cb392174
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spelling	oai:doaj.org-article:666aff1d5374431b9cb3e655cb3921742021-11-11T17:21:24ZOlaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells10.3390/ijms2221119381422-00671661-6596https://doaj.org/article/666aff1d5374431b9cb3e655cb3921742021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11938https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Glioblastoma represents the highest grade of brain tumors. Despite maximal resection surgery associated with radiotherapy and concomitant followed by adjuvant chemotherapy with temozolomide (TMZ), patients have a very poor prognosis due to the rapid recurrence and the acquisition of resistance to TMZ. Here, initially considering that TMZ is a prodrug whose activation is pH-dependent, we explored the contribution of glioblastoma cell metabolism to TMZ resistance. Using isogenic TMZ-sensitive and TMZ-resistant human glioblastoma cells, we report that the expression of O6-methylguanine DNA methyltransferase (MGMT), which is known to repair TMZ-induced DNA methylation, does not primarily account for TMZ resistance. Rather, fitter mitochondria in TMZ-resistant glioblastoma cells are a direct cause of chemoresistance that can be targeted by inhibiting oxidative phosphorylation and/or autophagy/mitophagy. Unexpectedly, we found that PARP inhibitor olaparib, but not talazoparib, is also a mitochondrial Complex I inhibitor. Hence, we propose that the anticancer activities of olaparib in glioblastoma and other cancer types combine DNA repair inhibition and impairment of cancer cell respiration.Luca X. ZampieriMartina SboarinaAndrea CacaceDebora GrassoLéopold ThabaultLoïc HamelinThibaut VazeilleElodie DumonRodrigue RossignolRaphaël FrédérickEtienne SonveauxFlorence LefrancPierre SonveauxMDPI AGarticleglioblastomachemoresistancetemozolomide (TMZ)cancer metabolismmitochondriaPARP inhibitorsBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11938, p 11938 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	glioblastoma chemoresistance temozolomide (TMZ) cancer metabolism mitochondria PARP inhibitors Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	glioblastoma chemoresistance temozolomide (TMZ) cancer metabolism mitochondria PARP inhibitors Biology (General) QH301-705.5 Chemistry QD1-999 Luca X. Zampieri Martina Sboarina Andrea Cacace Debora Grasso Léopold Thabault Loïc Hamelin Thibaut Vazeille Elodie Dumon Rodrigue Rossignol Raphaël Frédérick Etienne Sonveaux Florence Lefranc Pierre Sonveaux Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells
description	Glioblastoma represents the highest grade of brain tumors. Despite maximal resection surgery associated with radiotherapy and concomitant followed by adjuvant chemotherapy with temozolomide (TMZ), patients have a very poor prognosis due to the rapid recurrence and the acquisition of resistance to TMZ. Here, initially considering that TMZ is a prodrug whose activation is pH-dependent, we explored the contribution of glioblastoma cell metabolism to TMZ resistance. Using isogenic TMZ-sensitive and TMZ-resistant human glioblastoma cells, we report that the expression of O6-methylguanine DNA methyltransferase (MGMT), which is known to repair TMZ-induced DNA methylation, does not primarily account for TMZ resistance. Rather, fitter mitochondria in TMZ-resistant glioblastoma cells are a direct cause of chemoresistance that can be targeted by inhibiting oxidative phosphorylation and/or autophagy/mitophagy. Unexpectedly, we found that PARP inhibitor olaparib, but not talazoparib, is also a mitochondrial Complex I inhibitor. Hence, we propose that the anticancer activities of olaparib in glioblastoma and other cancer types combine DNA repair inhibition and impairment of cancer cell respiration.
format	article
author	Luca X. Zampieri Martina Sboarina Andrea Cacace Debora Grasso Léopold Thabault Loïc Hamelin Thibaut Vazeille Elodie Dumon Rodrigue Rossignol Raphaël Frédérick Etienne Sonveaux Florence Lefranc Pierre Sonveaux
author_facet	Luca X. Zampieri Martina Sboarina Andrea Cacace Debora Grasso Léopold Thabault Loïc Hamelin Thibaut Vazeille Elodie Dumon Rodrigue Rossignol Raphaël Frédérick Etienne Sonveaux Florence Lefranc Pierre Sonveaux
author_sort	Luca X. Zampieri
title	Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells
title_short	Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells
title_full	Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells
title_fullStr	Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells
title_full_unstemmed	Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells
title_sort	olaparib is a mitochondrial complex i inhibitor that kills temozolomide-resistant human glioblastoma cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/666aff1d5374431b9cb3e655cb392174
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Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells

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