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Lookup NU author(s): Dr Ian CowellORCiD, Professor Caroline AustinORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. Myeloperoxidase (MPO) is found almost exclusively in granulocytes and immature myeloid cells. It plays a key role in the innate immune system, catalysing the formation of reactive oxygen species that are important in anti-microbial action, but MPO also oxidatively transforms the topoisomerase II (TOP2) poison etoposide to chemical forms that have elevated DNA damaging properties. TOP2 poisons such as etoposide are widely used anti-cancer drugs, but they are linked to cases of secondary acute myeloid leukaemias through a mechanism that involves DNA damage and presumably erroneous repair leading to leukaemogenic chromosome translocations. This leads to the possibility that myeloperoxidase inhibitors could reduce the rate of therapy-related leukaemia by protecting haematopoietic cells from TOP2 poison-mediated genotoxic damage while preserving the anti-cancer efficacy of the treatment. We show here that myeloperoxidase inhibition reduces etoposide-induced TOP2B-DNA covalent complexes and resulting DNA double-strand break formation in primary ex vivo expanded CD34+ progenitor cells and unfractionated bone marrow mononuclear cells. Since MPO inhibitors are currently being developed as anti-inflammatory agents this raises the possibility that repurposing of these potential new drugs could provide a means of suppressing secondary acute myeloid leukaemias associated with therapies containing TOP2 poisons.
Author(s): Cowell IG, Austin CA
Publication type: Article
Publication status: Published
Journal: FEBS Open Bio
Year: 2024
Pages: ePub ahead of Print
Online publication date: 26/03/2024
Acceptance date: 20/03/2024
Date deposited: 17/04/2024
ISSN (electronic): 2211-5463
Publisher: John Wiley and Sons Ltd
URL: https://doi.org/10.1002/2211-5463.13799
DOI: 10.1002/2211-5463.13799
Data Access Statement: The data that support the findings of this study are available from the corresponding author caroline. austin@ncl.ac.uk upon reasonable request.
PubMed id: 38531625
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