Dysregulated lipid metabolism in TMZ-resistant glioblastoma: pathways, proteins, metabolites and therapeutic opportunities

Kao, Tzu-Jen; Lin, Chien-Liang; Yang, Wen Bin; Li, Hao-Yi; Hsu, Todd

doi:10.1186/s12944-023-01881-5

Cited by 10 publications

(2 citation statements)

References 99 publications

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“…This breakthrough enables the identification of lipid distributions and prospective targets for lipid-based therapy. A detailed examination of a GBM patient-derived xenograft (PDX) model, which included mass spectrometry imaging, histology, magnetic resonance imaging, phosphoproteomics, and mRNA sequencing, revealed that the distribution of the EGFR inhibitor erlotinib within intracranial tumors was insufficient to inhibit EGFR tyrosine kinase signaling, despite promising efficacy in vitro studies [ 164 , 165 ].…”

Section: Recent Advancements In Metabolic Reprogramming Of Gbm and Gscsmentioning

confidence: 99%

Progress in Glioma Stem Cell Research

Ramar,

Guo,

Hudson

et al. 2023

Cancers

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Glioblastoma multiforme (GBM) represents a diverse spectrum of primary tumors notorious for their resistance to established therapeutic modalities. Despite aggressive interventions like surgery, radiation, and chemotherapy, these tumors, due to factors such as the blood–brain barrier, tumor heterogeneity, glioma stem cells (GSCs), drug efflux pumps, and DNA damage repair mechanisms, persist beyond complete isolation, resulting in dismal outcomes for glioma patients. Presently, the standard initial approach comprises surgical excision followed by concurrent chemotherapy, where temozolomide (TMZ) serves as the foremost option in managing GBM patients. Subsequent adjuvant chemotherapy follows this regimen. Emerging therapeutic approaches encompass immunotherapy, including checkpoint inhibitors, and targeted treatments, such as bevacizumab, aiming to exploit vulnerabilities within GBM cells. Nevertheless, there exists a pressing imperative to devise innovative strategies for both diagnosing and treating GBM. This review emphasizes the current knowledge of GSC biology, molecular mechanisms, and associations with various signals and/or pathways, such as the epidermal growth factor receptor, PI3K/AKT/mTOR, HGFR/c-MET, NF-κB, Wnt, Notch, and STAT3 pathways. Metabolic reprogramming in GSCs has also been reported with the prominent activation of the glycolytic pathway, comprising aldehyde dehydrogenase family genes. We also discuss potential therapeutic approaches to GSC targets and currently used inhibitors, as well as their mode of action on GSC targets.

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Section: Recent Advancements In Metabolic Reprogramming Of Gbm and Gscsmentioning

confidence: 99%

Progress in Glioma Stem Cell Research

Ramar,

Guo,

Hudson

et al. 2023

Cancers

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“…These foci represent DSBs in a 1:1 ratio and can serve as biomarkers of damage [15][16] . However, the efficacy of TMZ typically diminishes with prolonged treatment time, closely associated with various mechanisms of resistance developed by tumor cells, such as enhanced DNA damage repair and dysregulation of cell cycle checkpoints [17][18][19] . Therefore, exploring novel anti-tumor mechanisms of TMZ and combining it with other strategies may help improve its efficacy and reverse resistance.…”

Section: Introductionmentioning

confidence: 99%

Investigation into the Effect and Mechanism of Temozolomide (TMZ) Inducing Ferroptosis to Inhibit Glioma Cell Proliferation

Yu,

Aisha,

Jing

et al. 2024

Preprint

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Although temozolomide (TMZ) is a first-line chemotherapeutic agent for treating malignant gliomas, its mechanisms of action remain incompletely understood, and primary or acquired resistance is prevalent in certain patients, severely limiting its clinical efficacy. Therefore, elucidating the molecular mechanisms underlying TMZ's mode of action is crucial for improving its therapeutic efficacy. This study aimed to delineate the effects of TMZ on glioma cells and the molecular mechanisms underlying its induction of ferroptosis. Using human glioma cell lines U87 and U251 as models, we systematically evaluated the impact of TMZ on cell proliferation, cell cycle, DNA integrity, and oxidative stress status through experiments including CCK-8, flow cytometry, and immunofluorescence. Further mechanistic investigations utilizing gene silencing and small molecule inducers elucidated the pivotal role of glutathione peroxidase 4 (GPX4) in the ferroptosis process induced by TMZ. Results demonstrated that TMZ inhibited glioma cell proliferation, induced cell cycle arrest and DNA damage, while concurrently promoting reactive oxygen species (ROS) accumulation and glutathione (GSH) depletion, along with downregulation of GPX4 expression. Ferroptosis inducers Erastin or RSL3 significantly augmented TMZ's cytotoxicity, exacerbating lipid peroxidation and GSH consumption. GPX4 gene silencing also enhanced TMZ's cytotoxic effects and synergistically interacted with Erastin to promote ferroptosis. Furthermore, knockdown of the GPX4 downstream target ATP-binding cassette transporter ABCC1 increased sensitivity to TMZ. This study unveiled a novel mechanism by which TMZ induces ferroptosis via the GPX4/ABCC1 pathway, providing important insights into understanding its molecular modes of action and improving clinical therapeutic efficacy.

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Mass Spectrometry Advances in Analysis of Glioblastoma

Al Shboul,

Singh,

Kobetic

et al. 2024

Mass Spectrometry Reviews

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Some cancers such as glioblastoma (GBM), show minimal response to medical interventions, often only capable of mitigating tumor growth or alleviating symptoms. High metabolic activity in the tumor microenvironment marked by immune responses and hypoxia, is a crucial factor driving tumor progression. The many developments in mass spectrometry (MS) over the last decades have provided a pivotal tool for studying proteins, along with their posttranslational modifications. It is known that the proteomic landscape of GBM comprises a wide range of proteins involved in cell proliferation, survival, migration, and immune evasion. Combination of MS imaging and microscopy has potential to reveal the spatial and molecular characteristics of pathological tissue sections. Moreover, integration of MS in the surgical process in form of techniques such as DESI‐MS or rapid evaporative ionization MS has been shown as an effective tool for rapid measurement of metabolite profiles, providing detailed information within seconds. In immunotherapy‐related research, MS plays an indispensable role in detection and targeting of cancer antigens which serve as a base for antigen‐specific therapies. In this review, we aim to provide detailed information on molecular profile in GBM and to discuss recent MS advances and their clinical benefits for targeting this aggressive disease.

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Dysregulated lipid metabolism in TMZ-resistant glioblastoma: pathways, proteins, metabolites and therapeutic opportunities

Cited by 10 publications

References 99 publications

Progress in Glioma Stem Cell Research

Progress in Glioma Stem Cell Research

Investigation into the Effect and Mechanism of Temozolomide (TMZ) Inducing Ferroptosis to Inhibit Glioma Cell Proliferation

Mass Spectrometry Advances in Analysis of Glioblastoma

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