Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells
Autor: | Florence Lefranc, Luca X Zampieri, Rodrigue Rossignol, Raphaël Frédérick, Debora Grasso, Thibaut Vazeille, Elodie Dumon, Loïc Hamelin, Martina Sboarina, Etienne Sonveaux, Andrea Cacace, Pierre Sonveaux, Léopold Thabault |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
cancer metabolism
Apoptosis temozolomide (TMZ) Piperazines chemistry.chemical_compound 0302 clinical medicine Mitophagy Tumor Cells Cultured Biology (General) PARP inhibitors Spectroscopy 0303 health sciences Brain Neoplasms chemoresistance General Medicine 3. Good health Computer Science Applications mitochondria Chemistry 030220 oncology & carcinogenesis PARP inhibitor DNA methylation medicine.drug QH301-705.5 Poly(ADP-ribose) Polymerase Inhibitors DNA methyltransferase Catalysis Article Olaparib Inorganic Chemistry 03 medical and health sciences Temozolomide medicine Humans Physical and Theoretical Chemistry QD1-999 Antineoplastic Agents Alkylating Molecular Biology Cell Proliferation 030304 developmental biology business.industry Organic Chemistry glioblastoma Cancer medicine.disease chemistry Drug Resistance Neoplasm Cancer cell Cancer research Phthalazines business metformin |
Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 21 International Journal of Molecular Sciences, Vol 22, Iss 11938, p 11938 (2021) |
ISSN: | 1422-0067 |
Popis: | 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. |
Databáze: | OpenAIRE |
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