Acquired temozolomide resistance in human glioblastoma cell line U251 is caused by mismatch repair deficiency and can be overcome by lomustine

Stritzelberger, Jenny; Distel, Luitpold; Buslei, Rolf; Fietkau, Rainer; Putz, Florian

doi:10.1007/s12094-017-1743-x

Cited by 41 publications

(39 citation statements)

References 38 publications

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“…In a mouse xenograft model of human GBM cell lines, McFaline-Figueroa et al found that MSH2 knockdown conferred TMZ resistance more potently than MSH6 knockdown [40]. In vitro experiments using U251 cells demonstrated that reductions in MLH1 expression drive destabilization of its binding partner PMS2, and may be more correlated with TMZ resistance than either MSH2 or MSH6 [41,42]. Our results are overall consistent with the preclinical studies pointing to the relative importance of MLH1.…”

Section: Discussionsupporting

confidence: 89%

Epigenetic preconditioning with decitabine sensitizes glioblastoma to temozolomide via induction of MLH1

Gallitto

Inocencio

et al. 2020

J Neurooncol

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Introduction To improve the standard treatment paradigm for glioblastoma (GBM), efforts have been made to explore the efficacy of epigenetic agents as chemosensitizers. Recent data suggest possible synergy between decitabine (DAC), a DNA hypomethylating agent, and temozolomide (TMZ) in GBM, but the mechanism remains unclear. The objective of this study was to determine the effects of DAC on TMZ sensitization in a consecutively derived set of primary GBM cultures, with a focus on mismatch repair (MMR) proteins. Methods Half maximal inhibitory concentrations (IC 50 ) of TMZ were calculated in eleven consecutive patient-derived GBM cell lines before and after preconditioning with DAC. MMR protein expression changes were determined by quantitative immunoblots and qPCR arrays. Single-molecule real-time (SMRT) sequencing of bisulfite (BS)-converted PCR amplicons of the MLH1 promoter was performed to determine methylation status. Results TMZ IC 50 significantly changed in 6 of 11 GBM lines of varying MGMT promoter methylation status in response to DAC preconditioning. Knockdown of MLH1 after preconditioning reversed TMZ sensitization. SMRT-BS sequencing of the MLH1 promoter region revealed higher levels of baseline methylation at proximal CpGs in desensitized lines compared to sensitized lines. Conclusions DAC enhances TMZ cytotoxicity in a subset of GBM cell lines, comprising lines both MGMT methylated and unmethylated tumors. This effect may be driven by levels of MLH1 via E2F1 transcription factor binding. Using unbiased long-range next-generation bisulfite-sequencing, we identified a region of the proximal MLH1 promoter with differential methylation patterns that has potential utility as a clinical biomarker for TMZ sensitization.

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Section: Discussionsupporting

confidence: 89%

Epigenetic preconditioning with decitabine sensitizes glioblastoma to temozolomide via induction of MLH1

Gallitto

Inocencio

et al. 2020

J Neurooncol

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“…Though the administration of TMZ has improved the prognosis of GBM patients, resistance against TMZ was quickly developed [9]. The overexpression of O 6 -methylguanine-DNA-methyltransferase (MGMT) is one of the main resistance mechanisms for repairing O 6 methylguanine, which is an important TMZ-induced lesion resulting in breakage of DNA double-strand and subsequent apoptosis [6,5]. In addition, immune escape after TMZ treatment [25], dysfunction of the DNA mismatch repair (MMR) system [1], as well as abnormal expression of nuclear factor erythroid 2related factor 2 (Nrf2) [26] and high expression of ATP-binding cassette (ABC) membrane transporters [2], were also demonstrated to be involved in resistance development.…”

Section: Discussionmentioning

confidence: 99%

“…Temozolomide (TMZ), a novel oral alkylating agent, is the drug that is most frequently used against malignant glioma, with broad-spectrum antitumor activity [5]. Although TMZ is considered the most promising chemotherapeutic drug against GBM, most patients suffer from tumor recurrence within 7 months due to the development of resistance [6]. Accumulating evidence demonstrates that the activation of protein kinase B (AKT) is responsible for the evolution of resistance in different types of cancers [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Amlexanox enhances temozolomide-induced anti-tumor effects in human glioblastoma cells by inhibiting IKBKE and the Akt-mTOR signaling pathway

Xiong

Guo

et al. 2020

Preprint

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Background: Temozolomide (TMZ), as the first-line chemotherapeutic agent for the treatment of glioblastoma multiforme (GBM), often fails to improve the prognosis of GBM patients due to the quick development of resistance. The need for more effective management of GBM is urgent. The aim of this study is to evaluate the efficacy of combined therapy with TMZ and amlexanox, a selective inhibitor of inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE), for GBM. Methods: in vitro, cell viability assay, apoptosis analysis, western blot, migration and invasion assay were used. In vivo, intracranial tumor models were constructed and the immunohistochemistry were used. Results: We found that combined treatment resulted in significant induction of cellular apoptosis and the inhibition of cell viability, migration and invasion in primary glioma cell and in the human glioma cell line, U87 MG. TMZ enhanced expression of phosphoration of adenosine 5‘-monophosphate-activated protein kinase (p-AMPK) and amlexanox led to reduction of IKBKE, with no impact on p-AMPK. Furthermore, we demonstrated that, compared to other groups treated with each component alone, TMZ combined with amlexanox effectively inhibited phosphorylation of protein kinase B (AKT) and mammalian target of rapamycin (mTOR). In addition, the combination treatment also clearly reduced in vivo tumor volume and prolonged median survival time in the xenograft mouse model. Conclusion: These results suggest that amlexanox sensitized primary glioma cell and U87 MG cell to TMZ at least partially though the suppression of IKBKE activation and the attenuation of AKT activation. Overall, combined treatment with TMZ and amlexanox may provide a promising possibility for improving the prognosis of glioblastoma patients in clinical practice.

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“…Notably, resistance is a complicated process involving de ciencies in apoptosis induction, activation of multiple signaling pathways and expulsion of drug through cell membrane transporters (38,40). Although novel therapeutic targets have been found in the past several decades, the overall survival of GBM patients remain dismal due to the tumor recurrence followed by chemoresistance (3,41). Therefore, developing new biomarkers and therapeutic strategies targeting TMZ resistance in GBM are in urgent need.…”

Section: Discussionmentioning

confidence: 99%

Loss of PLK2 induces acquired resistance to temozolomide in GBM via activation of Notch signaling

Alafate

et al. 2020

Preprint

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BackgroundGlioblastoma (GBM) is a lethal type of primary brain tumor with a median survival less than 15 months. Despite the recent improvements of comprehensive strategies, the outcomes for GBM patients remain dismal. Accumulating evidence indicates that rapid acquired chemoresistance is the major cause of GBM recurrence thus leads to worse clinical outcomes. Therefore, developing novel biomarkers and therapeutic targets for chemoresistant GBM is crucial for long-term cures. MethodsTranscriptomic profiles of glioblastoma were downloaded from gene expression omnibus (GEO) and TCGA database. Differentially expressed genes were analyzed and candidate gene PLK2 was selected for subsequent validation. Clinical samples and corresponding data were collected from our center and measured using immunohistochemistry analysis. Lentiviral transduction and in vivo xenograft transplantation were used to validate the bioinformatic findings. GSEA analyses were conducted to identify potential signaling pathways related to PLK2 expression and further confirmed by in vitro mechanistic assays. ResultsIn this study, we identified PLK2 as an extremely suppressed kinase-encoding gene in GBM samples, particularly in therapy resistant GBM. Additionally, reduced PLK2 expression implied poor prognosis and TMZ resistance in GBM patients. Functionally, up-regulated PLK2 attenuated cell proliferation, migration, invasion, and tumorigenesis of GBM cells. Besides, exogenous overexpression of PLK2 reduced acquired TMZ resistance of GBM cells. Furthermore, bioinformatics analysis indicated that PLK2 was negatively correlated with Notch signaling pathway in GBM. Mechanically, loss of PLK2 activated Notch pathway through negative transcriptional regulation of HES1 and degradation of Notch1.ConclusionLoss of PLK2 enhances aggressive biological behavior of GBM through activation of Notch signaling, indicating that PLK2 could be a prognostic biomarker and potential therapeutic target for chemoresistant GBM.

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Acquired temozolomide resistance in human glioblastoma cell line U251 is caused by mismatch repair deficiency and can be overcome by lomustine

Cited by 41 publications

References 38 publications

Epigenetic preconditioning with decitabine sensitizes glioblastoma to temozolomide via induction of MLH1

Epigenetic preconditioning with decitabine sensitizes glioblastoma to temozolomide via induction of MLH1

Amlexanox enhances temozolomide-induced anti-tumor effects in human glioblastoma cells by inhibiting IKBKE and the Akt-mTOR signaling pathway

Loss of PLK2 induces acquired resistance to temozolomide in GBM via activation of Notch signaling

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