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HPO iron chelator, CP655, causes the G1/S phase cell cycle block via p21 upregulation
Iron is known not only for its importance in cellular and metabolic pathways but also for its role in causing cellular toxicities such as production of reactive oxygen species and growth of pathogens. The inability of the human body to physiologically excrete excess iron highlights the need to devel...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654408/ https://www.ncbi.nlm.nih.gov/pubmed/32865890 http://dx.doi.org/10.1002/iid3.342 |
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author | Tewari, Damini Lloyd‐Jones, Katie Hider, Robert C. Collins, Helen |
author_facet | Tewari, Damini Lloyd‐Jones, Katie Hider, Robert C. Collins, Helen |
author_sort | Tewari, Damini |
collection | PubMed |
description | Iron is known not only for its importance in cellular and metabolic pathways but also for its role in causing cellular toxicities such as production of reactive oxygen species and growth of pathogens. The inability of the human body to physiologically excrete excess iron highlights the need to develop a cheap yet effective iron chelator. This study provides initial evidence of the therapeutic and prophylactic properties of 3‐hydroxypyridin‐4‐one (HPO) chelators in murine collagen‐induced arthritis. To determine whether these chelators would be effective on human cells, we tested a panel of different HPO chelators and identified 7‐diethylamino‐N‐((5‐hydroxy‐6‐methyl‐4‐oxo‐1,4‐dihydropyridin‐3‐yl)methyl)‐N‐methyl‐2‐oxo‐chromen‐3‐carboxamide (CP655) as the most effective compound targeting human CD4+ T cells. Treatment with CP655 causes significant inhibition of cell proliferation and production of inflammatory cytokines such as interferon‐γ and interleukin‐17. Microarray analysis revealed dysregulation in cell cycle‐related genes following CP655 treatment. This was validated by flow cytometry demonstrating a G1/S phase block caused by CP655. Finally, mechanistic experiments revealed that the chelator may be causing an upregulation of the cell cycle inhibitor protein CDKN1A (p21) as a possible mechanism of action. In conclusion, this study demonstrates that HPO chelators could prove to have therapeutic potential for diseases driven by excessive T cell proliferation. |
format | Online Article Text |
id | pubmed-7654408 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-76544082020-11-16 HPO iron chelator, CP655, causes the G1/S phase cell cycle block via p21 upregulation Tewari, Damini Lloyd‐Jones, Katie Hider, Robert C. Collins, Helen Immun Inflamm Dis Original Research Iron is known not only for its importance in cellular and metabolic pathways but also for its role in causing cellular toxicities such as production of reactive oxygen species and growth of pathogens. The inability of the human body to physiologically excrete excess iron highlights the need to develop a cheap yet effective iron chelator. This study provides initial evidence of the therapeutic and prophylactic properties of 3‐hydroxypyridin‐4‐one (HPO) chelators in murine collagen‐induced arthritis. To determine whether these chelators would be effective on human cells, we tested a panel of different HPO chelators and identified 7‐diethylamino‐N‐((5‐hydroxy‐6‐methyl‐4‐oxo‐1,4‐dihydropyridin‐3‐yl)methyl)‐N‐methyl‐2‐oxo‐chromen‐3‐carboxamide (CP655) as the most effective compound targeting human CD4+ T cells. Treatment with CP655 causes significant inhibition of cell proliferation and production of inflammatory cytokines such as interferon‐γ and interleukin‐17. Microarray analysis revealed dysregulation in cell cycle‐related genes following CP655 treatment. This was validated by flow cytometry demonstrating a G1/S phase block caused by CP655. Finally, mechanistic experiments revealed that the chelator may be causing an upregulation of the cell cycle inhibitor protein CDKN1A (p21) as a possible mechanism of action. In conclusion, this study demonstrates that HPO chelators could prove to have therapeutic potential for diseases driven by excessive T cell proliferation. John Wiley and Sons Inc. 2020-08-31 /pmc/articles/PMC7654408/ /pubmed/32865890 http://dx.doi.org/10.1002/iid3.342 Text en © 2020 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Research Tewari, Damini Lloyd‐Jones, Katie Hider, Robert C. Collins, Helen HPO iron chelator, CP655, causes the G1/S phase cell cycle block via p21 upregulation |
title | HPO iron chelator, CP655, causes the G1/S phase cell cycle block via p21 upregulation |
title_full | HPO iron chelator, CP655, causes the G1/S phase cell cycle block via p21 upregulation |
title_fullStr | HPO iron chelator, CP655, causes the G1/S phase cell cycle block via p21 upregulation |
title_full_unstemmed | HPO iron chelator, CP655, causes the G1/S phase cell cycle block via p21 upregulation |
title_short | HPO iron chelator, CP655, causes the G1/S phase cell cycle block via p21 upregulation |
title_sort | hpo iron chelator, cp655, causes the g1/s phase cell cycle block via p21 upregulation |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654408/ https://www.ncbi.nlm.nih.gov/pubmed/32865890 http://dx.doi.org/10.1002/iid3.342 |
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