Valproic Acid Enhanced Temozolomide-Induced Anticancer Activity in Human Glioma Through the p53–PUMA Apoptosis Pathway

Tsai, Hong-Chieh; Wei, Kuo‐Chen; Chen, Pin-Yuan; Huang, Chiung-Yin; Chen, Ko-Ting; Lin, Yi-Chin; Cheng, Hsiao-Wei; Chen, Yi-Rou; Wang, Hsiang‐Tsui

doi:10.3389/fonc.2021.722754

Cited by 15 publications

(13 citation statements)

References 80 publications

(101 reference statements)

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“…(18). VPA shows the ability to affect TMZ sensitivity in GBM cell lines suggesting that it is the chemosensitizing drug (54). Our experiments show that combined therapy with both drugs leads to total DNA hypomethylation, which suggests the lack of a clearly positive clinical effect of VPA in GBM.…”

Section: Discussionmentioning

confidence: 72%

“…The hypomethylation with TMZ in our experiments identifies possible obstacles to the combined therapy of temozolomide, a standard for chemotherapy of primary and recurrent GBM (53), with valproic acid, which is recommended in symptomatic tumorrelated epilepsy as a first-line treatment, especially during temozolomide therapy (1). Despite some cell lines studies showing a promising additive effect of VPA on TMZ (54)(55)(56), no significant positive impact on overall survival was observed in clinical trials while incorporating the VPA together with TMZ B A…”

Section: Discussionmentioning

confidence: 99%

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Cross-reactivity between histone demethylase inhibitor valproic acid and DNA methylation in glioblastoma cell lines

et al. 2022

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Currently, valproic acid (VPA) is known as an inhibitor of histone deacetylase (epigenetic drug) and is used for the clinical treatment of epileptic events in the course of glioblastoma multiforme (GBM). Which improves the clinical outcome of those patients. We analyzed the level of 5-methylcytosine, a DNA epigenetic modulator, and 8-oxodeoxyguanosine, an cellular oxidative damage marker, affected with VPA administration, alone and in combination with temozolomide (TMZ), of glioma (T98G, U118, U138), other cancer (HeLa), and normal (HaCaT) cell lines. We observed the VPA dose-dependent changes in the total DNA methylation in neoplastic cell lines and the lack of such an effect in a normal cell line. VPA at high concentrations (250-500 μM) induced hypermethylation of DNA in a short time frame. However, the exposition of GBM cells to the combination of VPA and TMZ resulted in DNA hypomethylation. At the same time, we observed an increase of genomic 8-oxo-dG, which as a hydroxyl radical reaction product with guanosine residue in DNA suggests a red-ox imbalance in the cancer cells and radical damage of DNA. Our data show that VPA as an HDAC inhibitor does not induce changes only in histone acetylation, but also changes in the state of DNA modification. It shows cross-reactivity between chromatin remodeling due to histone acetylation and DNA methylation. Finally, total DNA cytosine methylation and guanosine oxidation changes in glioma cell lines under VPA treatment suggest a new epigenetic mechanism of that drug action.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Cross-reactivity between histone demethylase inhibitor valproic acid and DNA methylation in glioblastoma cell lines

et al. 2022

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“…However, the beneficial effect of VPA on GBM progression in the clinic is extremely variable. A recent study inferred that wild-type p53 status is necessary for VPA to enhance the anti-neoplastic effect of TMZ, demonstrating a potential reason for inconsistencies seen within the literature (Tsai et al, 2021 ).…”

Section: From Laboratory To Clinical Translationmentioning

confidence: 99%

Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma

Hills

Kostarelos

Wykes

2022

Front. Mol. Neurosci.

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Glioblastoma (GBM) is the most common and advanced form of primary malignant tumor occurring in the adult central nervous system, and it is frequently associated with epilepsy, a debilitating comorbidity. Seizures are observed both pre- and post-surgical resection, indicating that several pathophysiological mechanisms are shared but also prompting questions about how the process of epileptogenesis evolves throughout GBM progression. Molecular mutations commonly seen in primary GBM, i.e., in PTEN and p53, and their associated downstream effects are known to influence seizure likelihood. Similarly, various intratumoral mechanisms, such as GBM-induced blood-brain barrier breakdown and glioma-immune cell interactions within the tumor microenvironment are also cited as contributing to network hyperexcitability. Substantial alterations to peri-tumoral glutamate and chloride transporter expressions, as well as widespread dysregulation of GABAergic signaling are known to confer increased epileptogenicity and excitotoxicity. The abnormal characteristics of GBM alter neuronal network function to result in metabolically vulnerable and hyperexcitable peri-tumoral tissue, properties the tumor then exploits to favor its own growth even post-resection. It is evident that there is a complex, dynamic interplay between GBM and epilepsy that promotes the progression of both pathologies. This interaction is only more complicated by the concomitant presence of spreading depolarization (SD). The spontaneous, high-frequency nature of GBM-associated epileptiform activity and SD-associated direct current (DC) shifts require technologies capable of recording brain signals over a wide bandwidth, presenting major challenges for comprehensive electrophysiological investigations. This review will initially provide a detailed examination of the underlying mechanisms that promote network hyperexcitability in GBM. We will then discuss how an investigation of these pathologies from a network level, and utilization of novel electrophysiological tools, will yield a more-effective, clinically-relevant understanding of GBM-related epileptogenesis. Further to this, we will evaluate the clinical relevance of current preclinical research and consider how future therapeutic advancements may impact the bidirectional relationship between GBM, SDs, and seizures.

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“…2-Ethylbutyric acid is structurally close to VPA, an anti-epileptic drug that is widely used to treat or prevent the perioperative seizures associated with GBM [ 20 ]. Among the postulated mechanisms of VPA action, the modulation of HDAC activity was confirmed [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…Among the postulated mechanisms of VPA action, the modulation of HDAC activity was confirmed [ 21 ]. As shown by Tsai et al [ 20 ], VPA potentiated temozolomide efficacy via downregulation of the O6-methylguanine-DNA methyltransferase (MGMT) enzyme expression, which plays an important role in cellular resistance to alkylating agents. It was also a potent cytotoxic agent in various cancer models [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

WP1234—A Novel Anticancer Agent with Bifunctional Activity in a Glioblastoma Model

et al. 2022

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Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis. Despite significant progress in drug development, the blood–brain barrier (BBB) continues to limit the use of novel chemotherapeutics. Thus, our attention has been focused on the design, synthesis, and testing of small-molecule anticancer agents that are able to penetrate the BBB. One such compound is the D-glucose analog, 2-deoxy-D-glucose (2-DG), which inhibits glycolysis and induces GBM cell death. 2-DG has already been tested in clinical trials but was not approved as a drug, in part due to inadequate pharmacokinetics. To improve the pharmacokinetic properties of 2-DG, a series of novel derivatives was synthesized. Herein, we report the biological effects of WP1234, a 2-ethylbutyric acid 3,6-diester of 2-DG that can potentially release 2-ethylbutyrate and 2-DG inside the cells when metabolized. Using biochemical assays and examining cell viability, proliferation, protein synthesis, and apoptosis induction, we assessed the cytotoxic potential of WP1234. WP1234 significantly reduced the viability of GBM cells in a dose- and time-dependent manner. The lactate and ATP synthesis assays confirmed the inhibition of glycolysis elicited by released 2-DG. Furthermore, an evaluation of histone deacetylases (HDAC) activity revealed that the 2-ethylbutyrate action resulted in HDAC inhibition. Overall, these results demonstrated that WP1234 is a bifunctional molecule with promising anticancer potential. Further experiments in animal models and toxicology studies are needed to evaluate the efficacy and safety of this new 2-DG derivative.

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Valproic Acid Enhanced Temozolomide-Induced Anticancer Activity in Human Glioma Through the p53–PUMA Apoptosis Pathway

Cited by 15 publications

References 80 publications

Cross-reactivity between histone demethylase inhibitor valproic acid and DNA methylation in glioblastoma cell lines

Cross-reactivity between histone demethylase inhibitor valproic acid and DNA methylation in glioblastoma cell lines

Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma

WP1234—A Novel Anticancer Agent with Bifunctional Activity in a Glioblastoma Model

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