DNA damage independent inhibition of NF-kB transcription by anthracyclines
- Universidade de Lisboa, Portugal
- Instituto Gulbenkian de Ciência, Portugal
- Helmholtz Zentrum München, Germany
- NOVA Medical School, Portugal
- European Molecular Biology Laboratory, Germany
- Cornell University, United States
- Jena University Hospital, Germany
- Leiden University Medical Center, Netherlands
- Technical University of Munich, Germany
Abstract
Anthracyclines are among the most used and effective anticancer drugs. Their activity has been attributed to DNA double-strand breaks resulting from topoisomerase II poisoning and to eviction of histones from select sites in the genome. Here we show that the extensively used anthracyclines Doxorubicin, Daunorubicin and Epirubicin decrease the transcription of nuclear factor kappa B (NF-κB)-dependent gene targets, but not interferon responsive genes in primary mouse (Mus musculus) macrophages. Using an NMR-based structural approach, we demonstrate that anthracyclines disturb the complexes formed between the NF-kB subunit RelA and its DNA binding sites. The anthracycline variants Aclarubicin, Doxorubicinone and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other anthracyclines but do not induce DNA damage, also suppressed inflammation, thus uncoupling DNA damage from the effects on inflammation. These findings have implications for anticancer therapy and for the development of novel anti-inflammatory drugs with limited side effects for life-threatening conditions such as sepsis.
Data availability
RNA-seq raw data of Murine Bone Marrow Derived Macrophages (BMDM's) stimulated with LPS and treated with PBS, Epirubicin and Aclarubicin and its analysis are available at https://github.com/andrebolerbarros/Chora_etal_2022 and https://zenodo.org/record/7389633
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Murine Bone Marrow Derived Macrophages (BMDM's) stimulated with LPS and treated with PBS, Epirubicin and Aclarubicinhttps://github.com/andrebolerbarros/Chora_etal_2022/tree/master/R_Analysis/metadata.
Article and author information
Author details
Sérgio Fernandes de Almeida
Funding
H2020 European Research Council (647888)
- Angelo Ferreira Chora
Fundação para a Ciência e a Tecnologia (PTDC/BIMMEC/ 4665/2014)
- Angelo Ferreira Chora
- Dora Pedroso
- Eleni Kyriakou
- Nadja Pejanovic
- Henrique Colaço
- Raffaella Gozzelino
- André Barros
- Katharina Willmann
- Tiago R Velho
- Catarina Moita
- Isa Santos
- Silvia Carvalho
- Filipa Batalha Martins
- João A Ferreira
- Sérgio Fernandes de Almeida
- Vladimir Benes
- Josef Anrather
- Sebastian Weis
- Miguel P Soares
- Arie Geerlof
- Jacques Neefjes
- Michael Sattler
- Ana C Messias
- Ana Neves Costa
- Luis F Moita
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal studies were performed in accordance with Portuguese regulations andapproved by the Instituto Gulbenkian de Ciência ethics committee and DGAV (A011_2019).
Copyright
© 2022, Chora et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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DNA damage independent inhibition of NF-kB transcription by anthracyclines
eLife 11:e77443.
https://doi.org/10.7554/eLife.77443
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