Metabolic changes in glioblastomas in response to choline kinase inhibition: In vivo MRS in rodent models

Bhaduri, Sourav; Kelly, Claire; Lesbats, Clémentine; Sharkey, Jack; Ressel, Lorenzo; Mukherjee, Soham; PLATT, M; Delikatny, Edward J.; Poptani, Harish

doi:10.1002/nbm.4855

Cited by 3 publications

(1 citation statement)

References 77 publications

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“…Studies have shown that the metabolite ratio has a specific value in differentiating treatment-related changes (radiation necrosis and tumor pseudoprogression) from tumor recurrence in gliomas [24][25][26]. Total choline (tCho) is considered a biomarker reflecting the state of cell membrane turnover and has been widely used to identify tumor areas with excessive cell proliferation and for the therapeutic monitoring of gliomas [27,28]. The product of the Warburg effect is lactate (Lac), whose level may reflect the metabolic characteristics of gliomas as they develop [29,30].…”

Section: Introductionmentioning

confidence: 99%

Using the metabolite alterations monitoring the AEG-1 expression level and cell biological behaviour of U251 cell in vitro

Sheng,

Yin,

Zeng

2023

PLoS ONE

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Astrocyte elevated gene-1 (AEG-1) is an important oncogene that overexpresses in gliomas and plays a vital role in their occurrence and progression. However, few reports have shown which biomarkers could reflect the level of AEG-1 expression in vivo so far. In recent years, intracellular metabolites monitored by proton magnetic resonance spectroscopy (1H MRS) as non-invasive imaging biomarkers have been applied to the precise diagnosis and therapy feedback of gliomas. Therefore, understanding the correlation between 1H MRS metabolites and AEG-1 gene expression in U251 cells may help to identify relevant biomarkers. This study constructed three monoclonal AEG-1-knockout U251 cell lines using the clustered regularly interspaced short palindromic repeat (CRISPR) /Cas9 technique and evaluated the biological behaviors and metabolite ratios of these cell lines. With the decline in AEG-1 expression, the apoptosis rate of the AEG-1-knockout cell lines increased. At the same time, the metastatic capacities decreased, and the relative contents of total choline (tCho) and lactate (Lac) were also reduced. In conclusion, deviations in AEG-1 expression influence the apoptosis rate and metastasis capacity of U251 cells, which the 1H MRS metabolite ratio could monitor. The tCho/creatinine(Cr) and Lac/Cr ratios positively correlated with the AEG-1 expression and malignant cell behavior. This study may provide potential biomarkers for accurate preoperative diagnosis and future AEG-1-targeting treatment evaluation of gliomas in vivo.

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Section: Introductionmentioning

confidence: 99%

Using the metabolite alterations monitoring the AEG-1 expression level and cell biological behaviour of U251 cell in vitro

Sheng,

Yin,

Zeng

2023

PLoS ONE

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Metabolic changes in glioblastomas in response to choline kinase inhibition: In vivo MRS in rodent models

et al. 2022

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Changes in glioblastoma (GBM) metabolism was investigated in response to JAS239, a choline kinase inhibitor, using MRS. In addition to the inhibition of phosphocholine synthesis, we investigated changes in other key metabolic pathways associated with GBM progression and treatment response. Three syngeneic rodent models of GBM were used: F98 (N = 12) and 9L (N = 8) models in rats and GL261 (N = 10) in mice. Rodents were intracranially injected with GBM cells in the right cortex and tumor growth was monitored using T2‐weighted images. Animals were treated once daily with intraperitoneal injections of 4 mg/kg JAS239 (F98 rats, n = 6; 9L rats, n = 6; GL261 mice, n = 5) or saline (control group, F98 rats, n = 6; 9L rats, n = 2; GL261 mice, n = 5) for five consecutive days. Single voxel spectra were acquired on Days 0 (T0, baseline) and 6 (T6, end of treatment) from the tumor as well as the contralateral normal brain using a PRESS sequence. Changes in metabolite ratios (tCho/tCr, tCho/NAA, mI/tCr, Glx/tCr and (Lip + Lac)/Cr) were used to assess metabolic pathway alterations in response to JAS239. Tumor growth arrest was noted in all models in response to JAS239 treatment compared with saline‐treated animals, with a significant reduction (p < 0.05) in the F98 model. A reduction in tCho/tCr was observed with JAS239 treatment in all GBM models, indicating reduced phospholipid metabolism, with the highest reduction in 9L followed by GL261 and F98 tumors. A significant reduction (p < 0.05) in the tCho/NAA ratio was observed in the 9L model. A significant reduction in mI/tCr (p < 0.05) was found in JAS239‐treated F98 tumors compared with the saline‐treated animals. A non‐significant trend of reduction in Glx/tCr was observed only in F98 and 9L tumors. JAS239‐treated F98 tumors also showed a significant increase in Lip + Lac (p < 0.05), indicating increased cell death. This study demonstrated the utility of MRS in assessing metabolic changes in GBM in response to choline kinase inhibition.

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Clinical Assessment of Magnetic Resonance Spectroscopy and Diffusion-Weighted Imaging in Diffuse Glioma: Insights Into Histological Grading and IDH Classification

Zhang,

Liu

et al. 2024

Can Assoc Radiol J

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Purpose: To assess the diagnostic utility of clinical magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI) in distinguishing between histological grading and isocitrate dehydrogenase ( IDH) classification in adult diffuse gliomas. Methods: A retrospective analysis was conducted on 247 patients diagnosed with adult diffuse glioma. Experienced radiologists evaluated DWI and MRS images. The Kruskal-Wallis test examined differences in DWI and MRS-related parameters across histological grades, while the Mann–Whitney U test assessed molecular classification. Receiver Operating Characteristic (ROC) curves evaluated parameter effectiveness. Survival curves, stratified by histological grade and IDH classification, were constructed using the Kaplan–Meier test. Results: The cohort comprised 141 males and 106 females, with ages ranging from 19 to 85 years. The Kruskal-Wallis test revealed significant differences in ADC mean, Cho/NAA, and Cho/Cr concerning glioma histological grade ( P < .01). Subsequent application of Dunn’s test showed significant differences in ADC mean among each histological grade ( P < .01). Notably, Cho/NAA exhibited a marked distinction between grade 2 and grade 3/4 gliomas ( P < .01). The Mann–Whitney U test indicated that only ADC mean showed statistical significance for IDH molecular classification ( P < .01). ROC curves were constructed to demonstrate the effectiveness of the specified parameters. Survival curves were also delineated to portray survival outcomes categorized by histological grade and IDH classification. Conclusions: Clinical MRS demonstrates efficacy in glioma histological grading but faces challenges in IDH classification. Clinical DWI’s ADC mean parameter shows significant distinctions in both histological grade and IDH classification.

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Metabolic changes in glioblastomas in response to choline kinase inhibition: In vivo MRS in rodent models

Cited by 3 publications

References 77 publications

Using the metabolite alterations monitoring the AEG-1 expression level and cell biological behaviour of U251 cell in vitro

Using the metabolite alterations monitoring the AEG-1 expression level and cell biological behaviour of U251 cell in vitro

Metabolic changes in glioblastomas in response to choline kinase inhibition: In vivo MRS in rodent models

Clinical Assessment of Magnetic Resonance Spectroscopy and Diffusion-Weighted Imaging in Diffuse Glioma: Insights Into Histological Grading and IDH Classification

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