Olaparib is a mitochondrial Complex I inhibitor that kills temozolomide-resistant human glioblastoma cells
(2021) International Journal of Molecular Sciences — Vol. 22, n° 11938, p. 17 (2021)
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- 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 TMZinduced 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
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Zampieri, L., Sboarina, M., Cacace, A., Grasso, D., Thabault, L., Hamelin, L., Vazeille, T., Dumon, E., Rossignol, R., Frédérick, R., Sonveaux, E., Lefranc, F., & Sonveaux, P. (2021). Olaparib is a mitochondrial Complex I inhibitor that kills temozolomide-resistant human glioblastoma cells. International Journal of Molecular Sciences, 22(11938), 17. https://doi.org/10.3390/ijms222111938 (Original work published 2021)