Lomeguatrib Increases the Radiosensitivity of MGMT Unmethylated Human Glioblastoma Multiforme Cell Lines.

Anna Kirstein,Daniela Schilling,Thomas E Schmid,Stephanie E Combs

doi:10.3390/ijms22136781

Abstract

Background: Treatment resistance of glioblastoma multiforme to chemo- and radiotherapy remains a challenge yet to overcome. In particular, the O6-methylguanine-DNA-methyltransferase (MGMT) promoter unmethylated patients have only little benefit from chemotherapy treatment using temozolomide since MGMT counteracts its therapeutic efficacy. Therefore, new treatment options in radiotherapy need to be developed to inhibit MGMT and increase radiotherapy response. Methods: Lomeguatrib, a highly specific MGMT inhibitor, was used to inactivate MGMT protein in vitro. Radiosensitivity of established human glioblastoma multiforme cell lines in combination with lomeguatrib was investigated using the clonogenic survival assay. Inhibition of MGMT was analyzed using Western Blot. Cell cycle distribution and apoptosis were investigated to determine the effects of lomeguatrib alone as well as in combination with ionizing radiation. Results: Lomeguatrib significantly decreased MGMT protein and reduced radiation-induced G2/M arrest. A radiosensitizing effect of lomeguatrib was observed when administered at 1 µM and increased radioresistance at 20 µM. Conclusion: Low concentrations of lomeguatrib elicit radiosensitization, while high concentrations mediate a radioprotective effect.

Highlights

Accepted: 22 June 2021Glioblastoma multiforme (GBM) is still one of the most devastating diagnoses
Colony-forming assay (CFA) was performed in order to determine the radiosensitivity of established human glioblastoma multiforme cell lines
Despite advances in finding predictive biomarkers, such as MGMT promoter methylation status, the five-year survival is still less than 3%, making

Summary

Introduction

Accepted: 22 June 2021Glioblastoma multiforme (GBM) is still one of the most devastating diagnoses. A total of 90% of all glioblastoma are primary GBM, with a median overall survival of 15 months and a median age at diagnosis of 62 years [3]. It develops de novo within 3–6 months from glial progenitor cells [4]. Secondary GBM, in contrast, is less common with a median overall survival of 31 months and a median age at diagnosis of 44 years [3]. Originating from low-grade astrocytomas (WHO grade II) and anaplastic astrocytomas (WHO grade III), secondary GBM develops over several years [4]

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