Temozolomide is additive with cytotoxic effect of irradiation in canine glioma cell lines

Tresch, Nina Simona; Fuchs, Daniel; Morandi, Luca; Tonon, Caterina; Bley, Carla Rohrer; Nytko, Katarzyna J.

doi:10.1002/vms3.620

Cited by 6 publications

(15 citation statements)

References 52 publications

(75 reference statements)

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“…Each next-generation sequencing (NGS) experiment was designed to allocate at least 1000 reads/region, with an expected depth of coverage of at least 1000×. FASTQ files were processed in a Galaxy Project environment following a pipeline as described previously (Tresch et al, 2021). In brief, after filtering for quality >Q30 and for read lengths (>80 bp), FASTQ files were then mapped by BWAmeth to generate BAM (Binary Alignment Map) files, which were then in turn processed by MethylDackel using CanFam3.1 as reference genome.…”

Section: Genomic Dna Isolation and Methylation Analysismentioning

confidence: 99%

“…Western Blot analysis was used to assess the protein expression levels and was performed as previously described (Tresch et al, 2021).…”

Section: Western Blotmentioning

confidence: 99%

“…In a recent study, TMZ in combination with IR had an additive effect in different canine glioma cells (Tresch et al, 2021). Both, TMZ and CCNU, penetrate the blood-brain barrier, and therapeutic dosing has been determined for dogs (Gustafson & Bailey, 2020;Marconato et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Triple combination of lomustine, temozolomide and irradiation reduces canine glioma cell survival in vitro

Fuchs

Bley

Morandi

et al. 2023

Veterinary Medicine & Sci

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Background: Combined chemoradiation offers a promising therapeutic strategy for dogs with glioma. The alkylating agents temozolomide (TMZ) and lomustine (CCNU) penetrate the blood-brain barrier, and doses for dogs are established. Whether such combinations are clinically advantageous remains to be explored together with tumour-specific markers.Objective: To investigate if triple combination of lomustine, temozolomide and irradiation reduces canine glioma cell survival in vitro. Methods:We evaluated the sensitising effect of CCNU alone and in combination with TMZ-irradiation in canine glioma J3T-BG cells and long-term drug-exposed subclones by using clonogenic survival and proliferation assays. Bisulphite-SEQ and Western Blot were used to investigate molecular alterations.Results: TMZ (200 μM) or CCNU alone (5 μM) reduced the irradiated survival fraction (4 Gy) from 60% to 38% (p = 0.0074) and 26% (p = 0.0002), respectively. The doubledrug combination reduced the irradiated survival fraction (4 Gy) more potently to 12% (p < 0.0001).After long-term drug exposure, both subclones show higher IC 50 values against CCNU and TMZ. For CCNU-resistant cells, both, single-drug CCNU (p = 0.0006) and TMZ (p = 0.0326) treatment combined with irradiation (4 Gy) remained effective. The doubledrug-irradiation combination reduced the cell survival by 86% (p < 0.0001), compared to 92% in the parental (nonresistant) cell line. For TMZ-resistant cells, only the doubledrug combination with irradiation (4 Gy) reduced the cell survival by 88% (p = 0.0057) while single-drug treatment lost efficacy.Chemoresistant cell lines demonstrated higher P-gp expression while MGMTmethylation profile analysis showed a general high methylation level in the parental and long-term treated cell lines. Conclusions:Our findings indicate that combining CCNU with TMZ-irradiation significantly reduces canine glioma cell survival. Such a combination could overcome current challenges of therapeutic resistance to improve overall patient survival.

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Section: Genomic Dna Isolation and Methylation Analysismentioning

confidence: 99%

“…Western Blot analysis was used to assess the protein expression levels and was performed as previously described (Tresch et al, 2021).…”

Section: Western Blotmentioning

confidence: 99%

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Triple combination of lomustine, temozolomide and irradiation reduces canine glioma cell survival in vitro

Fuchs

Bley

Morandi

et al. 2023

Veterinary Medicine & Sci

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“…Libraries were generated using the same approach for mutation analysis with two PCR steps. FASTQ files were processed in a Galaxy Project environment following a pipeline described previously [44], in brief after filtering for quality > Q30 and for read lengths (> 80 bp), FASTQ files were then mapped by BWAmeth. BAM files were then in turn processed by MethylDackel using human GRCh38/hg38 as reference genome.…”

Section: Dna Mutation and Methylation Analysismentioning

confidence: 99%

Impact of phospholipase C β1 in glioblastoma: a study on the main mechanisms of tumor aggressiveness

Ratti

Marvi

Mongiorgi

et al. 2022

Cell. Mol. Life Sci.

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Glioblastoma represents the most lethal brain tumor in adults. Several studies have shown the key role of phospholipase C β1 (PLCβ1) in the regulation of many mechanisms within the central nervous system suggesting PLCβ1 as a novel signature gene in the molecular classification of high-grade gliomas. This study aims to determine the pathological impact of PLCβ1 in glioblastoma, confirming that PLCβ1 gene expression correlates with glioma’s grade, and it is lower in 50 glioblastoma samples compared to 20 healthy individuals. PLCβ1 silencing in cell lines and primary astrocytes, leads to increased cell migration and invasion, with the increment of mesenchymal transcription factors and markers, as Slug and N-Cadherin and metalloproteinases. Cell proliferation, through increased Ki-67 expression, and the main survival pathways, as β-catenin, ERK1/2 and Stat3 pathways, are also affected by PLCβ1 silencing. These data suggest a potential role of PLCβ1 in maintaining a normal or less aggressive glioma phenotype.

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“…DNA methylation was evaluated using targeted bisulfite NGS for MGMT promoter (coordinates on chromosome 10: 129466810-129467529, reference hg38), generating libraries with the same approach for mutation analysis. FASTQ files were processed in a Galaxy Project environment using BWAmeth and MethylDackel, taking the human GRCh38/hg38 as the reference genome (52).…”

Section: Tumor Histopathological and Molecular Characterizationmentioning

confidence: 99%

Neuroplasticity Mechanisms in Frontal Brain Gliomas: A Preliminary Study

et al. 2022

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BackgroundPathological brain processes may induce adaptive cortical reorganization, however, the mechanisms underlying neuroplasticity that occurs in the presence of lesions in eloquent areas are not fully explained. The aim of this study was to evaluate functional compensatory cortical activations in patients with frontal brain gliomas during a phonemic fluency task and to explore correlations with cognitive performance, white matter tracts microstructural alterations, and tumor histopathological and molecular characterization.MethodsFifteen patients with frontal glioma were preoperatively investigated with an MRI study on a 3T scanner and a subgroup underwent an extensive neuropsychological assessment. The hemispheric laterality index (LI) was calculated through phonemic fluency task functional MRI (fMRI) activations in the frontal, parietal, and temporal lobe parcellations. Diffusion-weighted images were acquired for all patients and for a group of 24 matched healthy volunteers. Arcuate Fasciculus (AF) and Frontal Aslant Tract (FAT) tractography was performed using constrained spherical deconvolution diffusivity modeling and probabilistic fiber tracking. All patients were operated on with a resective aim and underwent adjuvant therapies, depending on the final diagnosis.ResultsAll patients during the phonemic fluency task fMRI showed left hemispheric dominance in temporal and parietal regions. Regarding frontal regions (i.e., frontal operculum) we found right hemispheric dominance that increases when considering only those patients with tumors located on the left side. These latter activations positively correlate with verbal and visuo-spatial short-term memory, and executive functions. No correlations were found between the left frontal operculum and cognitive performance. Furthermore, patients with IDH-1 mutation and without TERT mutation, showed higher rightward frontal operculum fMRI activations and better cognitive performance in tests measuring general cognitive abilities, semantic fluency, verbal short-term memory, and executive functions. As for white matter tracts, we found left and right AF and FAT microstructural alterations in patients with, respectively, left-sided and right-side glioma compared to controls.ConclusionsCompensatory cortical activation of the corresponding region in the non-dominant hemisphere and its association with better cognitive performance and more favorable histopathological and molecular tumor characteristics shed light on the neuroplasticity mechanisms that occur in the presence of a tumor, helping to predict the rate of post-operative deficit, with the final goal of improving patients'quality of life.

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Temozolomide is additive with cytotoxic effect of irradiation in canine glioma cell lines

Cited by 6 publications

References 52 publications

Triple combination of lomustine, temozolomide and irradiation reduces canine glioma cell survival in vitro

Triple combination of lomustine, temozolomide and irradiation reduces canine glioma cell survival in vitro

Impact of phospholipase C β1 in glioblastoma: a study on the main mechanisms of tumor aggressiveness

Neuroplasticity Mechanisms in Frontal Brain Gliomas: A Preliminary Study

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