Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells.

Luca X Zampieri,Florence Lefranc,Loïc Hamelin,Rodrigue Rossignol,Martina Sboarina,Debora Grasso,Etienne Sonveaux,Andrea Cacace,Léopold Thabault,Thibaut Vazeille,Elodie Dumon,Pierre Sonveaux,Raphaël Frédérick

doi:10.3390/ijms222111938

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 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.

Highlights

Glioblastomas (GBMs) account for ~50% of all brain tumors in humans [1]
We have previously shown that long-term treatment of two human GBM cell lines of astrocytic origin, U373 and T98G, with TMZ induced the expression of the glucose transporter GLUT3 [21], suggesting that acquired resistance to TMZ could be associated with a switch to a more glycolytic metabolism
We report that (i) the methylguanine DNA methyltransferase (MGMT) inhibitor O6BG and PARP inhibitors (PARPi) olaparib and talazoparib inhibited the clonogenic survival of human GBM cells independently of their sensitivity to TMZ, (ii) the autophagy/mitophagy inhibitor CQ selectively re-sensitized

Summary

Introduction

Glioblastomas (GBMs) account for ~50% of all brain tumors in humans [1] They represent the ultimate grade of brain cancer and are associated with a very poor prognosis, with a mean survival time of only a few months despite surgery, radiotherapy, and chemotherapy [2,3]. It is a prodrug that requires a two-step conversion: it is first hydrolyzed to form intermediate compound monomethyl-triazeno-imidazole-carboxamide (MTIC), which breaks down to form the reactive methyldiazonium ion [8] This conversion is pH-dependent and does not require enzymatic activation: TMZ is stable/inactive at acidic pH but decomposes to MTIC at pH > 7; and MTIC is stable/inactive at alkaline pH, but fragments to produce a methyldiazonium ion at pH < 7 [9,10] (Figure S1a). O6-methylguanine methylation is the primary cause of TMZ-induced cytotoxicity

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Discussion

Conclusion