To be Wild or Mutant: Role of Isocitrate Dehydrogenase 1 (IDH1) and 2-Hydroxy Glutarate (2-HG) in Gliomagenesis and Treatment Outcome in Glioma

Bhavya, Bharathan; Anand, C.R.; Madhusoodanan, U.K.; Rajalakshmi, P; Krishnakumar, K.; Easwer, H. V.; Deepti, Ayswaria; Gopala, Srinivas

doi:10.1007/s10571-019-00730-3

Cited by 25 publications

(22 citation statements)

References 90 publications

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“…NAD (+)-dependent IDHs in the mitochondria play a pivotal role in the production of NADH from NAD+ in the Krebs cycle. As reviewed before, IDH mutations inhibit glioma stem cells' differentiation by producing high levels of 2-hydroxyglutaric acid (2-HG), regulate vascular endothelial growth factor (VEGF) to promote the formation of the tumor microenvironment, and induce high levels of hypoxia-inducible factor-1α (HIF-1α) to promote glioma invasion [117]. IDH mutations also repress the tumor-associated immune system by inhibiting complement activation, while reducing the number of tumor-infiltrating T cells, phagocytosis and the excretion of cytokines.…”

Section: Resveratrol In Brain Cancer Studiesmentioning

confidence: 99%

The Plant-Derived Compound Resveratrol in Brain Cancer: A Review

et al. 2020

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Despite intensive research, malignant brain tumors are among the most difficult to treat due to high resistance to conventional therapeutic approaches. High-grade malignant gliomas, including glioblastoma and anaplastic astrocytoma, are among the most devastating and rapidly growing cancers. Despite the ability of standard treatment agents to achieve therapeutic concentrations in the brain, malignant gliomas are often resistant to alkylating agents. Resveratrol is a plant polyphenol occurring in nuts, berries, grapes, and red wine. Resveratrol crosses the blood‒brain barrier and may influence the central nervous system. Moreover, it influences the enzyme isocitrate dehydrogenase and, more importantly, the resistance to standard treatment via various mechanisms, such as O6-methylguanine methyltransferase. This review summarizes the anticancer effects of resveratrol in various types of brain cancer. Several in vitro and in vivo studies have presented promising results; however, further clinical research is necessary to prove the therapeutic efficacy of resveratrol in brain cancer treatment.

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Section: Resveratrol In Brain Cancer Studiesmentioning

confidence: 99%

The Plant-Derived Compound Resveratrol in Brain Cancer: A Review

et al. 2020

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“…Among gliomas, somatic mutations in the genes IDH1 and 2 occur in about 80% of grade II-III gliomas and secondary glioblastoma (GBM), while they are very rare in grade IV glioblastomas [44]. In fact, IDH1 and IDH2 mutations correlate with a better overall survival of glioma patients.…”

Section: Reports About Reduced M 6 a Rna Methylation In Glioblastomamentioning

confidence: 99%

Insights into the Regulatory Role of m6A Epitranscriptome in Glioblastoma

Galardi

Michienzi

Ciafrè

2020

IJMS

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N6-methyladenosine (m6A) is one of the most widespread and abundant internal messenger RNA modifications found in eukaryotes. Emerging evidence suggests that this modification is strongly linked to the activation and inhibition of cancer pathways and is associated with prognostically significant tumour subtypes. The present review describes the dynamic nature of m6A regulator enzymes, as methyltransferases, demethylases and m6A binding proteins, and points out thevalue of the balance among these proteins in regulating gene expression, cell metabolism and cancer development. The main focus of this review is on the roles of m6A modification in glioblastoma, the most aggressive and invariably lethal brain tumour. Although the study of m6A in glioblastoma is a young one, and papers in this field can yield divergent conclusions, the results collected so far clearly demonstrate that modulation of mRNA m6A levels impacts multiple aspects of this tumour, including growth, glioma stem cells self-renewal, and tumorigenesis, suggesting that mRNA m6A modification may serve as a promising target for glioblastoma therapy. We also present recent data about another type of epitranscriptomic modification, the methylation of cytosine at a specific site of 28S rRNA, as it was recently shown to affect the biology of glioma cells, with high potential of clinical implications.

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“…All three isoforms convert isocitrate to α-ketoglutarate (α-KG) by oxidative decarboxylation [15]. To date, in human gliomas, only heterozygotic mutations in IDH-1 and IDH-2 have been reported, with a significant preponderance of IDH-1 [6,16]. Around 90% of IDH-1 mutated (IDHmut) gliomas involve a substitution in the catalytic site of arginine-132, which is replaced by histidine (IDH1 R132H mutation) [6].…”

Section: Introductionmentioning

confidence: 99%

Non-Invasive Prediction of IDH Mutation in Patients with Glioma WHO II/III/IV Based on F-18-FET PET-Guided In Vivo 1H-Magnetic Resonance Spectroscopy and Machine Learning

Bumes

Wirtz

Fellner

et al. 2020

Cancers

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Isocitrate dehydrogenase (IDH)-1 mutation is an important prognostic factor and a potential therapeutic target in glioma. Immunohistological and molecular diagnosis of IDH mutation status is invasive. To avoid tumor biopsy, dedicated spectroscopic techniques have been proposed to detect D-2-hydroxyglutarate (2-HG), the main metabolite of IDH, directly in vivo. However, these methods are technically challenging and not broadly available. Therefore, we explored the use of machine learning for the non-invasive, inexpensive and fast diagnosis of IDH status in standard 1H-magnetic resonance spectroscopy (1H-MRS). To this end, 30 of 34 consecutive patients with known or suspected glioma WHO grade II-IV were subjected to metabolic positron emission tomography (PET) imaging with O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) for optimized voxel placement in 1H-MRS. Routine 1H-magnetic resonance (1H-MR) spectra of tumor and contralateral healthy brain regions were acquired on a 3 Tesla magnetic resonance (3T-MR) scanner, prior to surgical tumor resection and molecular analysis of IDH status. Since 2-HG spectral signals were too overlapped for reliable discrimination of IDH mutated (IDHmut) and IDH wild-type (IDHwt) glioma, we used a nested cross-validation approach, whereby we trained a linear support vector machine (SVM) on the complete spectral information of the 1H-MRS data to predict IDH status. Using this approach, we predicted IDH status with an accuracy of 88.2%, a sensitivity of 95.5% (95% CI, 77.2–99.9%) and a specificity of 75.0% (95% CI, 42.9–94.5%), respectively. The area under the curve (AUC) amounted to 0.83. Subsequent ex vivo 1H-nuclear magnetic resonance (1H-NMR) measurements performed on metabolite extracts of resected tumor material (eight specimens) revealed myo-inositol (M-ins) and glycine (Gly) to be the major discriminators of IDH status. We conclude that our approach allows a reliable, non-invasive, fast and cost-effective prediction of IDH status in a standard clinical setting.

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To be Wild or Mutant: Role of Isocitrate Dehydrogenase 1 (IDH1) and 2-Hydroxy Glutarate (2-HG) in Gliomagenesis and Treatment Outcome in Glioma

Cited by 25 publications

References 90 publications

The Plant-Derived Compound Resveratrol in Brain Cancer: A Review

The Plant-Derived Compound Resveratrol in Brain Cancer: A Review

Insights into the Regulatory Role of m6A Epitranscriptome in Glioblastoma

Non-Invasive Prediction of IDH Mutation in Patients with Glioma WHO II/III/IV Based on F-18-FET PET-Guided In Vivo 1H-Magnetic Resonance Spectroscopy and Machine Learning

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