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- Title
Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells.
- Authors
Zampieri, Luca X.; Sboarina, Martina; Cacace, Andrea; Grasso, Debora; Thabault, Léopold; Hamelin, Loïc; Vazeille, Thibaut; Dumon, Elodie; Rossignol, Rodrigue; Frédérick, Raphaël; Sonveaux, Etienne; Lefranc, Florence; Sonveaux, Pierre
- Abstract
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.
- Subjects
O6-Methylguanine-DNA Methyltransferase; DNA repair; CELL respiration; OLAPARIB; OXIDATIVE phosphorylation; GLIOBLASTOMA multiforme; BRAIN tumors
- Publication
International Journal of Molecular Sciences, 2021, Vol 22, Issue 21, p11938
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms222111938