Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells.
Luca X ZampieriMartina SboarinaAndrea CacaceDebora GrassoLéopold ThabaultLoïc HamelinThibaut VazeilleElodie DumonRodrigue RossignolRaphaël FrederickEtienne SonveauxFlorence LefrancPierre SonveauxPublished in: International journal of molecular sciences (2021)
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.
Keyphrases
- poor prognosis
- induced apoptosis
- dna repair
- cell cycle arrest
- oxidative stress
- dna methylation
- endothelial cells
- cell death
- dna damage
- endoplasmic reticulum stress
- signaling pathway
- newly diagnosed
- long non coding rna
- minimally invasive
- end stage renal disease
- induced pluripotent stem cells
- radiation therapy
- chronic kidney disease
- squamous cell carcinoma
- cell therapy
- stem cells
- rectal cancer
- cell proliferation
- young adults
- resistance training
- papillary thyroid
- cell free
- coronary artery bypass
- mesenchymal stem cells
- lymph node metastasis
- single molecule
- drug induced
- drug delivery
- circulating tumor cells
- pi k akt