Cargando…
The Interaction of the Flavonoid Fisetin with Human Glutathione Transferase A1-1
Glutathione transferases (GSTs) are a family of Phase II detoxification enzymes that are involved in the development of the multidrug resistance (MDR) mechanism in cancer cells and therefore affect the clinical outcome of cancer chemotherapy. The discovery of nontoxic natural compounds as inhibitors...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004991/ https://www.ncbi.nlm.nih.gov/pubmed/33806779 http://dx.doi.org/10.3390/metabo11030190 |
_version_ | 1783672030856478720 |
---|---|
author | Alqarni, Mohammed Hamed Foudah, Ahmed Ibrahim Muharram, Magdy Mohamed Labrou, Nikolaos E. |
author_facet | Alqarni, Mohammed Hamed Foudah, Ahmed Ibrahim Muharram, Magdy Mohamed Labrou, Nikolaos E. |
author_sort | Alqarni, Mohammed Hamed |
collection | PubMed |
description | Glutathione transferases (GSTs) are a family of Phase II detoxification enzymes that are involved in the development of the multidrug resistance (MDR) mechanism in cancer cells and therefore affect the clinical outcome of cancer chemotherapy. The discovery of nontoxic natural compounds as inhibitors for GSTs is a promising approach for chemosensitizing and reversing MDR. Fisetin (7,3′,4′-flavon-3-ol) is a plant flavonol present in many plants and fruits. In the present work, the interaction of fisetin with human glutathione transferase A1-1 (hGSTA1-1) was investigated. Kinetic analysis revealed that fisetin is a reversible inhibitor for hGSTA1-1 with IC(50) 1.2 ± 0.1 μΜ. It functions as a mixed-type inhibitor toward glutathione (GSH) and as a noncompetitive inhibitor toward the electrophile substrate 1-chloro-2,4-dinitrobenzene (CDNB). In silico molecular modeling and docking predicted that fisetin binds at a distinct location, in the solvent channel of the enzyme, and occupies the entrance of the substrate-binding sites. Treatment of proliferating human epithelial colorectal adenocarcinoma cells (CaCo-2) with fisetin causes a reduction in the expression of hGSTA1-1 at the mRNA and protein levels. In addition, fisetin inhibits GST activity in CaCo-2 cell crude extract with an IC(50) (2.5 ± 0.1 μΜ), comparable to that measured using purified recombinant hGSTA1-1. These actions of fisetin can provide a synergistic role toward the suppression and chemosensitization of cancer cells. The results of the present study provide insights into the development of safe and effective GST-targeted cancer chemosensitizers. |
format | Online Article Text |
id | pubmed-8004991 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-80049912021-03-29 The Interaction of the Flavonoid Fisetin with Human Glutathione Transferase A1-1 Alqarni, Mohammed Hamed Foudah, Ahmed Ibrahim Muharram, Magdy Mohamed Labrou, Nikolaos E. Metabolites Article Glutathione transferases (GSTs) are a family of Phase II detoxification enzymes that are involved in the development of the multidrug resistance (MDR) mechanism in cancer cells and therefore affect the clinical outcome of cancer chemotherapy. The discovery of nontoxic natural compounds as inhibitors for GSTs is a promising approach for chemosensitizing and reversing MDR. Fisetin (7,3′,4′-flavon-3-ol) is a plant flavonol present in many plants and fruits. In the present work, the interaction of fisetin with human glutathione transferase A1-1 (hGSTA1-1) was investigated. Kinetic analysis revealed that fisetin is a reversible inhibitor for hGSTA1-1 with IC(50) 1.2 ± 0.1 μΜ. It functions as a mixed-type inhibitor toward glutathione (GSH) and as a noncompetitive inhibitor toward the electrophile substrate 1-chloro-2,4-dinitrobenzene (CDNB). In silico molecular modeling and docking predicted that fisetin binds at a distinct location, in the solvent channel of the enzyme, and occupies the entrance of the substrate-binding sites. Treatment of proliferating human epithelial colorectal adenocarcinoma cells (CaCo-2) with fisetin causes a reduction in the expression of hGSTA1-1 at the mRNA and protein levels. In addition, fisetin inhibits GST activity in CaCo-2 cell crude extract with an IC(50) (2.5 ± 0.1 μΜ), comparable to that measured using purified recombinant hGSTA1-1. These actions of fisetin can provide a synergistic role toward the suppression and chemosensitization of cancer cells. The results of the present study provide insights into the development of safe and effective GST-targeted cancer chemosensitizers. MDPI 2021-03-23 /pmc/articles/PMC8004991/ /pubmed/33806779 http://dx.doi.org/10.3390/metabo11030190 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ). |
spellingShingle | Article Alqarni, Mohammed Hamed Foudah, Ahmed Ibrahim Muharram, Magdy Mohamed Labrou, Nikolaos E. The Interaction of the Flavonoid Fisetin with Human Glutathione Transferase A1-1 |
title | The Interaction of the Flavonoid Fisetin with Human Glutathione Transferase A1-1 |
title_full | The Interaction of the Flavonoid Fisetin with Human Glutathione Transferase A1-1 |
title_fullStr | The Interaction of the Flavonoid Fisetin with Human Glutathione Transferase A1-1 |
title_full_unstemmed | The Interaction of the Flavonoid Fisetin with Human Glutathione Transferase A1-1 |
title_short | The Interaction of the Flavonoid Fisetin with Human Glutathione Transferase A1-1 |
title_sort | interaction of the flavonoid fisetin with human glutathione transferase a1-1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004991/ https://www.ncbi.nlm.nih.gov/pubmed/33806779 http://dx.doi.org/10.3390/metabo11030190 |
work_keys_str_mv | AT alqarnimohammedhamed theinteractionoftheflavonoidfisetinwithhumanglutathionetransferasea11 AT foudahahmedibrahim theinteractionoftheflavonoidfisetinwithhumanglutathionetransferasea11 AT muharrammagdymohamed theinteractionoftheflavonoidfisetinwithhumanglutathionetransferasea11 AT labrounikolaose theinteractionoftheflavonoidfisetinwithhumanglutathionetransferasea11 AT alqarnimohammedhamed interactionoftheflavonoidfisetinwithhumanglutathionetransferasea11 AT foudahahmedibrahim interactionoftheflavonoidfisetinwithhumanglutathionetransferasea11 AT muharrammagdymohamed interactionoftheflavonoidfisetinwithhumanglutathionetransferasea11 AT labrounikolaose interactionoftheflavonoidfisetinwithhumanglutathionetransferasea11 |