Overexpression of Glutathione S-Transferases in Human Diseases: Drug Targets and Therapeutic Implications

Lv, Ning; Huang, Chunyan; Huang, Haoyan; Dong, Zhiqiang; Chen, Xijing; Lu, Chengcan; Zhang, Yongjie

doi:10.3390/antiox12111970

Cited by 10 publications

(2 citation statements)

References 204 publications

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“…Regarding multidrug resistance (MDR), hGSTA1-1 has been shown to be strongly involved in the detoxification of chlorambucil by catalyzing the GSH conjugation reaction of this drug, thereby reducing its effectiveness. Similarly, resistance to bacitracin, melphalan, thiotepa, cyclophosphamide, imatinib, and cisplatin has been partially attributed to the activity of hGSTA1-1 [ 24 ].…”

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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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: 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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“…The transporter is capable of the rapid removal of anticancer drugs from target tumor cells [ 27 ]. Glutathione S-transferase has been reported to be important for the development of anticancer drug resistance through detoxification [ 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

In Silico Analysis of Novel Bacterial Metabolites with Anticancer Activities

Maumela,

Serepa-Dlamini

2024

Metabolites

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Resistance to anticancer therapeutics is a major global concern. Thus, new anticancer agents should be aimed against novel protein targets to effectively mitigate the increased resistance. This study evaluated the potential of secondary metabolites from a bacterial endophyte, as new anticancer agents, against a novel protein target, fibroblast growth factor. In silico genomic characterization of the Bacillus sp. strain MHSD_37 was used to identify potential genes involved in encoding secondary metabolites with biological activity. The strain was also exposed to stress and liquid chromatography–mass spectrometry used for the identification and annotation of secondary metabolites of oligopeptide class with anticancer activity. Selected metabolites were evaluated for their anticancer activity through molecular docking and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties analysis. Phylogenetic analysis revealed that strain MHSD_37 shared close evolutionary relationships with Bacillus at the species level, with no identified relationships at the sub-species level. Both in silico genomic characterization and spectrometry analysis identified secondary metabolites with potential anticancer activity. Molecular docking analysis illustrated that the metabolites formed complexes with the target protein, fibroblast growth factor, which were stabilized by hydrogen bonds. Moreover, the ADMET analysis showed that the metabolites passed the toxicity test for use as a potential drug. Thereby, Bacillus sp. strain MHSD_37 is a potential novel strain with oligopeptide metabolites that can be used as new anticancer agents against novel protein targets.

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Serving up health: How phytochemicals transform food into medicine in the battle against cancer

Sharma,

Tewari,

Sati

et al. 2024

Food Frontiers

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The escalating global cancer burden underscores the urgent need for more effective therapeutic strategies. Phytochemicals, naturally occurring compounds in plants, have garnered attention for their potential in cancer chemoprevention and chemotherapy. Their ability to modulate molecular mechanisms and influence cell signaling pathways offers a promising avenue for cancer management. This review aims to synthesize current knowledge on phytochemicals’ chemopreventive and chemotherapeutic potential, focusing on their molecular mechanisms of action and impacts on cell signaling pathways involved in cancer. A systematic literature search was conducted across major databases, including PubMed/Medline, Web of Science, Scopus, and Google Scholar. The search strategy uses Medical Subject Headings (MeSH) and free‐text terms using Boolean operators to capture relevant studies. Inclusion criteria targeted original research and reviews on the effects of phytochemicals in cancer, with a specific focus on molecular mechanisms. Phytochemicals, including flavonoids, polyphenols, and terpenoids, demonstrated significant anticancer properties by inducing cell cycle arrest, apoptosis, and autophagy. They modulate critical cell signaling pathways, such as cyclooxygenase‐2, nuclear factor kappa B, and various growth factor‐related pathways, and rectify epigenetic alterations, contributing to their chemopreventive and therapeutic effects. Phytochemicals represent a valuable resource for developing novel cancer prevention and treatment strategies; their actions on molecular mechanisms and cell signaling pathways underscore their potential in cancer prevention and combat. Further research is warranted to translate these findings into clinical applications, optimizing phytochemical‐based interventions for cancer management.

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Overexpression of Glutathione S-Transferases in Human Diseases: Drug Targets and Therapeutic Implications

Cited by 10 publications

References 204 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

In Silico Analysis of Novel Bacterial Metabolites with Anticancer Activities

Serving up health: How phytochemicals transform food into medicine in the battle against cancer

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