Characterization of Temozolomide Resistance Using a Novel Acquired Resistance Model in Glioblastoma Cell Lines

Temozolomide (TMZ) is the first line of standard therapy in glioblastoma (GBM). However, relapse occurs due to TMZ resistance. We attempted to establish an acquired TMZ resistance model that recapitulates the TMZ resistance phenotype and the relevant gene signature. Two GBM cell lines received two c...

Full description

Saved in:
Bibliographic Details
Published in:Cancers 2022-04, Vol.14 (9), p.2211
Main Authors: Zhu, Yuan, Chen, Zhen, Kim, Su Na, Gan, Chao, Ryl, Tatsiana, Lesjak, Michaela Silvia, Rodemerk, Jan, Zhong, Rong De, Wrede, Karsten, Dammann, Philipp, Sure, Ulrich
Format: Article
Language:English
Subjects:
Apoptosis
Brain cancer
Brain tumors
Cell culture
Cell cycle
Cell self-renewal
Chemoresistance
Chemotherapy
Cytotoxicity
Deoxyribonucleic acid
DNA
DNA biosynthesis
DNA damage
Flow cytometry
Glioblastoma
Medical prognosis
Mismatch repair
MSH2 protein
MSH6 protein
Phenotypes
Radiation
Replication
Stem cells
Temozolomide
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Temozolomide (TMZ) is the first line of standard therapy in glioblastoma (GBM). However, relapse occurs due to TMZ resistance. We attempted to establish an acquired TMZ resistance model that recapitulates the TMZ resistance phenotype and the relevant gene signature. Two GBM cell lines received two cycles of TMZ (150 µM) treatment for 72 h each. Regrown cells (RG2) were defined as TMZ resistant cells. MTT assay revealed significantly less susceptibility and sustained growth of RG2 compared with parental cells after TMZ challenge. TMZ-induced DNA damage significantly decreased in 53BP1-foci reporter transduced-RG2 cells compared with parental cells, associated with downregulation of and . Flow cytometry revealed reduced G2/M arrest, increased EdU incorporation and suppressed apoptosis in RG2 cells after TMZ treatment. Colony formation and neurosphere assay demonstrated enhanced clonogenicity and neurosphere formation capacity in RG2 cells, accompanied by upregulation of stem markers. Collectively, we established an acute TMZ resistance model that recapitulated key features of TMZ resistance involving impaired mismatch repair, redistribution of cell cycle phases, increased DNA replication, reduced apoptosis and enhanced self-renewal. Therefore, this model may serve as a promising research tool for studying mechanisms of TMZ resistance and for defining therapeutic approaches to GBM in the future.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers14092211