Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Tewari, Damini, Lloyd‐Jones, Katie, Hider, Robert C., Collins, Helen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
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
_version_ 1783608062527930368
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
work_keys_str_mv AT tewaridamini hpoironchelatorcp655causestheg1sphasecellcycleblockviap21upregulation
AT lloydjoneskatie hpoironchelatorcp655causestheg1sphasecellcycleblockviap21upregulation
AT hiderrobertc hpoironchelatorcp655causestheg1sphasecellcycleblockviap21upregulation
AT collinshelen hpoironchelatorcp655causestheg1sphasecellcycleblockviap21upregulation