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
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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