| Naslov: | A monocarbonyl curcuminoid derivative inhibits the activity of human glutathione transferase A4-4 and chemosensitizes glioblastoma cells to temozolomide |
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| Avtorji: | ID Tsouri, Steliana (Avtor)
ID Tselo, Evanthia (Avtor)
ID Premetis, Georgios E. (Avtor)
ID Furlan, Veronika (Avtor)
ID Pantiora, Panagiota D. (Avtor)
ID Mavroidi, Barbara (Avtor)
ID Matiadis, Dimitris (Avtor)
ID Pelecanou, Maria (Avtor)
ID Papageorgiou, Anastassios C. (Avtor)
ID Bren, Urban (Avtor)
ID Sagnou, Marina (Avtor)
ID Labrou, Nikolaos E. (Avtor) |
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| Datoteke: |  pharmaceuticals-17-00365.pdf (2,60 MB)
MD5: 883DA237082809904AC84E53C55D2B36
 https://www.mdpi.com/1424-8247/17/3/365
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| Jezik: | Angleški jezik |
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| Vrsta gradiva: | Članek v reviji |
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| Tipologija: | 1.01 - Izvirni znanstveni članek |
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| Organizacija: | FKKT - Fakulteta za kemijo in kemijsko tehnologijo
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| Opis: | 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 µM and 16.9 ± 0.4 µM, 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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| Ključne besede: | chemosensitization, chemoresistance, curcumin, glioblastoma, human glutathione transferase A4-4, ellagic acid, monocarbonyl curcumin derivatives, GST inhibition, temozolomide sensitization |
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| Status publikacije: | Objavljeno |
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| Verzija publikacije: | Objavljena publikacija |
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| Poslano v recenzijo: | 19.02.2024 |
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| Datum sprejetja članka: | 07.03.2024 |
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| Datum objave: | 11.03.2024 |
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| Založnik: | MDPI |
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| Leto izida: | 2024 |
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| Št. strani: | 18 str. |
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| Številčenje: | let. 17, št. 3, št. članka 365 |
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| PID: | 20.500.12556/DKUM-90145  |
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| UDK: | 577 |
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| COBISS.SI-ID: | 189586435 |
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| DOI: | 10.3390/ph17030365 |
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| ISSN pri članku: | 1424-8247 |
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| Avtorske pravice: | © 2024 by the authors
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| Datum objave v DKUM: | 23.08.2024 |
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| Število ogledov: | 170 |
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| Število prenosov: | 37 |
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| Metapodatki: |    |
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| Področja: | Ostalo
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