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Olaparib is a mitochondrial complex i inhibitor that kills temozolomide-resistant human glioblastoma cells

par Zampieri, Luca L.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
Référence International journal of molecular sciences, 22, 21, 11938
Publication Publié, 2021-11

Article révisé par les pairs

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Résumé :

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.