ABT-888 restores sensitivity in temozolomide resistant glioma cells and xenografts

PloS One
Alice L YuanMichael D Blough

Abstract

Temozolomide (TMZ) is active against glioblastomas (GBM) in which the O6-methylguanine-DNA methyltransferase (MGMT) gene is silenced. However, even in responsive cases, its beneficial effect is undermined by the emergence of drug resistance. Here, we tested whether inhibition of poly (ADP-ribose) polymerase-1 and -2 (PARP) enhanced the effectiveness of TMZ. Using patient derived brain tumor initiating cells (BTICs) and orthotopic xenografts as models of newly diagnosed and recurrent high-grade glioma, we assessed the effects of TMZ, ABT-888, and the combination of TMZ and ABT-888 on the viability of BTICs and survival of tumor-bearing mice. We also studied DNA damage repair, checkpoint protein phosphorylation, and DNA replication in mismatch repair (MMR) deficient cells treated with TMZ and TMZ plus ABT-888. Cells and xenografts derived from newly diagnosed MGMT methylated high-grade gliomas were sensitive to TMZ while those derived from unmethylated and recurrent gliomas were typically resistant. ABT-888 had no effect on the viability of BTICs or tumor bearing mice, but co-treatment with TMZ restored sensitivity in resistant cells and xenografts from newly diagnosed unmethylated gliomas and recurrent gliomas with MSH6 mutation...Continue Reading

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Citations

Jun 21, 2020·Journal of Neuro-oncology·Alice L YuanMichael D Blough
Apr 17, 2020·Neuro-oncology·Alexandra K BohmGregory Cairncross
Sep 15, 2020·Neuro-oncology·Julie J Miller, Daniel P Cahill
Nov 2, 2019·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Joseph A RossNehal Thakor
Jan 5, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Fumi HiguchiDaniel P Cahill
Nov 5, 2019·Biochemical and Biophysical Research Communications·Lin ChangYali Liu
Feb 16, 2021·Frontiers in Oncology·Ricardo Gómez-OlivaNoelia Geribaldi-Doldán
Feb 18, 2020·Trends in Cancer·Jianfang Ning, Hiroaki Wakimoto
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Aug 31, 2021·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Leonardo Delello Di FilippoMarlus Chorilli

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Datasets Mentioned

BETA
ABT-888

Methods Mentioned

BETA
xenografts
xenograft
electrophoresis

Clinical Trials Mentioned

NCT02152982

Software Mentioned

Comet

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