Curzerene suppresses progression of human glioblastoma through inhibition of glutathione S‐transferase A4

Cheng, Bo; Hong, Xiaoliang; Wang, Linfang; Cao, Yuanyuan; Qin, Deng-li; Zhou, Han; Gao, Dianshuai

doi:10.1111/cns.13800

Cited by 8 publications

(8 citation statements)

References 53 publications

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“…Following our initial observation that DM148 barely inhibited the enzyme, whereas the DM151 was the most potent inhibitor of all tested monocarbonyl compounds, exhibiting a low micromolar IC 50 value of 2.4 μΜ, their cytotoxicity effect against two glioblastoma cell lines, namely U-251 MG and U-87 MG, was evaluated. Both cell lines have been previously reported to overexpress hGSTA4-4, and downregulation by curzerene resulted in growth and invasion inhibition [ 34 ]. Similarly, it was hypothesized that this extreme difference in hGSTA4-4 inhibitory potential between DM148 and DM151 could also differentiate their cytotoxic effects.…”

Section: Resultsmentioning

confidence: 99%

“…Curcumin is the primary constituent of turmeric ( Curcuma longa ) extract, which contains numerous active compounds, among which curzerene, a sesquiterpene, has been shown to downregulate the expression of human hGSTA1-1 in lung cancer, resulting in tumor inhibition [ 33 ]. Curcumin is also among the very few reported compounds that inhibit in vitro the expression of hGSTA4-4 [ 34 ]. Interestingly, treatment of glioblastoma cells with curzerene resulted in lower expression of hGSTA4 mRNA and protein leading to a time-and dose-dependent manner inhibition of the proliferation, invasion, and migration of the cells.…”

Section: Introductionmentioning

confidence: 99%

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A Monocarbonyl Curcuminoid Derivative Inhibits the Activity of Human Glutathione Transferase A4-4 and Chemosensitizes Glioblastoma Cells to Temozolomide

Tsouri,

Tselo,

Premetis

et al. 2024

Pharmaceuticals

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Human glutathione transferase A4-4 (hGSTA4-4) displays high catalytic efficiency towards 4-hydroxyalkenals and other cytotoxic and mutagenic products of radical reactions and lipid peroxidation. Its role as a target for the chemosensitization of cancer cells has not been investigated so far. In this study, the inhibitory potency of twelve selected natural products and ten monocarbonyl curcumin derivatives against hGSTA4-4 was studied. Among natural products, ellagic acid turned out to be the strongest inhibitor with an IC50 value of 0.44 ± 0.01 μM. Kinetic analysis using glutathione (GSH) and 1-chloro-2,4-dinitrobenzene (CDNB) as variable substrates showed that ellagic acid behaved as a competitive inhibitor towards both GSH and CDNB, with Ki values of 0.39 ± 0.02 and 0.63 ± 0.03 μM, respectively. Among the curcumin derivatives studied, three proved to be the most potent inhibitors, in the order DM151 > DM101 > DM100, with IC50 values of 2.4 ± 0.1 μM, 12.7 ± 1.1 μΜ and 16.9 ± 0.4 μΜ, respectively. Further kinetic inhibition analysis of the most active derivative, DM151, demonstrated that this compound is a mixed inhibitor towards CDNB with inhibition constants of Ki = 4.1 ± 0.5 μM and Ki’ = 0.536 ± 0.034 μM, while it is a competitive inhibitor towards GSH with a Ki = 0.98 ± 0.11 μM. Molecular docking studies were performed to interpret the differences in binding of ellagic acid and curcumin derivatives to hGSTA4-4. The in silico measured docking scores were consistent with the obtained experimental data. Hydrogen bonds appear to be the main contributors to the specific binding of monocarbonyl curcumin derivatives, while π-π stacking interactions play a key role in the enzyme–ellagic acid interaction. In vitro cytotoxicity assessment of the worst (DM148) and the best (DM151) inhibitors was performed against glioblastoma cell lines U-251 MG and U-87 MG. The results revealed that DM151 displays considerably higher cytotoxicity against both glioblastoma cell lines, while the glioblastoma cytotoxicity of DM148 was very limited. Furthermore, low and non-toxic doses of DM151 sensitized U-251 MG cells to the first-line glioblastoma chemotherapeutic temozolomide (TMZ), allowing us to propose for the first time that hGSTA4-4 inhibitors may be attractive therapeutic partners for TMZ to optimize its clinical effect in glioblastoma chemotherapy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Monocarbonyl Curcuminoid Derivative Inhibits the Activity of Human Glutathione Transferase A4-4 and Chemosensitizes Glioblastoma Cells to Temozolomide

Tsouri,

Tselo,

Premetis

et al. 2024

Pharmaceuticals

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“…GSTA4 is a phase 2 detoxifying enzyme that modulates cell proliferation and apoptosis by regulating lipid peroxidation. Previous studies have reported that decreased expression of GSTA4 is associated with positive outcomes in glioma models ( Cheng et al, 2022 ), whereas increased expression of GSTA4 promotes the malignant progression of liver cancer ( Liu et al, 2017 ). Notably, GSTA4 is involved in SMC proliferation ( Luo et al, 2018 ) and may thus play a vital role in the pathological process of IA.…”

Section: Discussionmentioning

confidence: 99%

“…By catalyzing conjugation reactions of metabolites of lipid peroxidation to glutathione (GSH), GSTA4 participates in regulating cell proliferation and apoptosis ( Laborde, 2010 ). GSTA4 is expressed in the cerebral cortex and brainstem and is involved in the development of gliomas ( Cheng et al, 2022 ). Overexpression of human GSTA4 in carotid arteries can reduce neointimal formation after carotid allografts ( Xu et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

DNA methylation and mRNA expression of glutathione S-transferase alpha 4 are associated with intracranial aneurysms in a gender-dependent manner

Yu²,

Zhou³

et al. 2023

Front. Genet.

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Objective: We performed a case-control study to investigate the correlation between DNA methylation and mRNA expression of the glutathione S-transferase alpha 4 (GSTA4) gene and the risk of intracranial aneurysm (IA) in the Chinese Han population.Methods: After propensity score matching, 44 pairs of cases and controls were collected in this study. Fasting blood samples were collected for DNA and RNA extraction within 24 h of admission. Nine CpG dinucleotides were selected from the GSTA4 promoter region for DNA methylation pyrosequencing. mRNA expression of GSTA4 was measured by quantitative real-time polymerase chain reaction (RT-qPCR). In vitro cell experiments were conducted to verify the association between 5-aza-2′-deoxycytidine induced DNA hypomethylation and GSTA4 mRNA expression.Results: The mean methylation level of GSTA4 was much lower in IA patients, especially in IA patients, especially in unruptured IA (UIA), than that in controls (IA vs. Control, p < .001; ruptured IA (RIA) vs. Control, p = .005; UIA vs. Control, p < .001). With sex stratification, we further found that the association between GSTA4 methylation and IA risk presented only in women (mean methylation level: IA vs. Control, p < .001; RIA vs. Control, p = .009; UIA vs. Control, p < .001). GSTA4 mRNA expression was significantly higher in the IA group than in the control group (p < .01) and negatively correlated with DNA methylation in all individuals (r = −.746, p < .001). DNA hypomethylation can increase GSTA4 mRNA expression in human primary artery smooth muscle cells. The receiver operating characteristic (ROC) curve showed that GSTA4 mean methylation (AUC = .80, p < .001) was a reliable predictor of women intracranial aneurysm, among which CpG 1 exhibited the best predictive value (AUC = .89, p < .001). In addition, GSTA4 expression levels could also predict the risk of IA in women (AUC = .87, p = .005).Conclusion: Decreased DNA methylation and increased mRNA expression of the GSTA4 gene are associated with the risk of IA in women.

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“…It was reported that MMP is localized in vasculature cells and tumour cells of malignant astrocytomas 145 . MMP inhibition significantly decreases invasion, migration and tumour progression in advanced glioma cells 146 . All of the tumour cells would upregulate glycolysis to reduce the energy supplied by mitochondrial.…”

Section: Tumour Microenvironment Is the Main Medium For The Prolifera...mentioning

confidence: 99%

Proton pump inhibitors display anti‐tumour potential in glioma

Rao

2022

Cell Proliferation

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Objectives: Glioma is one of the most aggressive brain tumours with poor overall survival despite advanced technology in surgical resection, chemotherapy and radiation.Progression and recurrence are the hinge causes of low survival. Our aim is to explain the concrete mechanism in the proliferation and progression of tumours based on tumour microenvironment (TME). The main purpose is to illustrate the mechanism of proton pump inhibitors (PPIs) in affecting acidity, hypoxia, oxidative stress, inflammatory response and autophagy based on the TME to induce apoptosis and enhance the sensitivity of chemoradiotherapy.Findings: TME is the main medium for tumour growth and progression. Acidity, hypoxia, inflammatory response, autophagy, angiogenesis and so on are the main causes of tumour progress. PPIs, as a common clinical drug to inhibit gastric acid secretion, have the advantages of fast onset, long action time and small adverse reactions.Nowadays, several kinds of literature highlight the potential of PPIs in inhibiting tumour progression. However, long-term use of PPIs alone also has obvious side effects. Therefore, till now, how to apply PPIs to promote the effect of radiochemotherapy and find the concrete dose and concentration of combined use are novel challenges.Conclusions: PPIs display the potential in enhancing the sensitivity of chemoradiotherapy to defend against glioma based on TME. In the clinic, it is also necessary to explore specific concentrations and dosages in synthetic applications. | BACKGROUNDGlioma is one of the most aggressive brain tumours. Histologically, the World Health Organization (WHO) classified the tumours of the central nervous system (CNS) into astrocytomas, oligodendrogliomas and ependymoma. In addition, gliomas are classified into four grades according to the degree of malignancy. Types I and II are low-grade gliomas and types III and IV are high-grade gliomas. [1][2][3] The clinical cure rate and 5-year survival rate of patients are all very low. The prognosis is very dismal and the average survival period is only about 1 year. One of the main reasons for the poor prognosis of patients is that glioma is prone to drug resistance to chemoradiation therapy resistance. 4,5 Therefore, it is urgent to explore new strategies for glioma treatment.Pump proton inhibitors (PPIs) are a drug of choice for inhibiting gastric acid secretion. In clinical, they are the first-line option to treat peptic ulcers, gastroesophageal reflux disease, zoai syndrome and upper gastrointestinal bleeding. 6,7 It has become the first-line drug for abnormal gastric acid secretion and related diseases combined with amoxicillin, clarithromycin and other drugs to treat Helicobacter pylori infection. 8,9 PPIs have the advantages of fast onset, strong acid inhibition, long action time, low blood drug concentration and low

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Curzerene suppresses progression of human glioblastoma through inhibition of glutathione S‐transferase A4

Cited by 8 publications

References 53 publications

A Monocarbonyl Curcuminoid Derivative Inhibits the Activity of Human Glutathione Transferase A4-4 and Chemosensitizes Glioblastoma Cells to Temozolomide

A Monocarbonyl Curcuminoid Derivative Inhibits the Activity of Human Glutathione Transferase A4-4 and Chemosensitizes Glioblastoma Cells to Temozolomide

DNA methylation and mRNA expression of glutathione S-transferase alpha 4 are associated with intracranial aneurysms in a gender-dependent manner

Proton pump inhibitors display anti‐tumour potential in glioma

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