دورية أكاديمية
Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells
| العنوان: | Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells |
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| المؤلفون: | 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 |
| المصدر: | International Journal of Molecular Sciences, Vol 22, Iss 21, p 11938 (2021) |
| بيانات النشر: | MDPI AG, 2021. |
| سنة النشر: | 2021 |
| المجموعة: | LCC:Biology (General) LCC:Chemistry |
| مصطلحات موضوعية: | glioblastoma, chemoresistance, temozolomide (TMZ), cancer metabolism, mitochondria, PARP inhibitors, Biology (General), QH301-705.5, Chemistry, QD1-999 |
| الوصف: | 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1422-0067 1661-6596 |
| Relation: | https://www.mdpi.com/1422-0067/22/21/11938; https://doaj.org/toc/1661-6596; https://doaj.org/toc/1422-0067 |
| DOI: | 10.3390/ijms222111938 |
| URL الوصول: | https://doaj.org/article/666aff1d5374431b9cb3e655cb392174 |
| رقم الأكسشن: | edsdoj.666aff1d5374431b9cb3e655cb392174 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 14220067 16616596 |
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| DOI: | 10.3390/ijms222111938 |