DNA damage independent inhibition of NF-kB transcription by anthracyclines

  1. Angelo Ferreira Chora
  2. Dora Pedroso
  3. Eleni Kyriakou
  4. Nadja Pejanovic
  5. Henrique Colaço
  6. Raffaella Gozzelino
  7. André Barros
  8. Katharina Willmann
  9. Tiago R Velho
  10. Catarina Moita
  11. Isa Santos
  12. Pedro Pereira
  13. Silvia Carvalho
  14. Filipa Batalha Martins
  15. João A Ferreira
  16. Sérgio Fernandes de Almeida
  17. Vladimir Benes
  18. Josef Anrather
  19. Sebastian Weis
  20. Miguel P Soares
  21. Arie Geerlof
  22. Jacques Neefjes
  23. Michael Sattler
  24. Ana C Messias  Is a corresponding author
  25. Ana Neves Costa  Is a corresponding author
  26. Luis F Moita  Is a corresponding author
  1. Universidade de Lisboa, Portugal
  2. Instituto Gulbenkian de Ciência, Portugal
  3. Helmholtz Zentrum München, Germany
  4. NOVA Medical School, Portugal
  5. European Molecular Biology Laboratory, Germany
  6. Cornell University, United States
  7. Jena University Hospital, Germany
  8. Leiden University Medical Center, Netherlands
  9. 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

The following data sets were generated

Article and author information

Author details

  1. Angelo Ferreira Chora

    Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  2. Dora Pedroso

    Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5735-5094
  3. Eleni Kyriakou

    Institute of Structural Biology, Helmholtz Zentrum München, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Nadja Pejanovic

    Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  5. Henrique Colaço

    Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2026-0163
  6. Raffaella Gozzelino

    NOVA Medical School, Lisboa, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  7. André Barros

    Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  8. Katharina Willmann

    Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  9. Tiago R Velho

    Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0455-8189
  10. Catarina Moita

    Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9910-2343
  11. Isa Santos

    Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  12. Pedro Pereira

    Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  13. Silvia Carvalho

    Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  14. Filipa Batalha Martins

    Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  15. João A Ferreira

    Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  16. Sérgio Fernandes de Almeida

    Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7774-1355
  17. Vladimir Benes

    Genomics Core Facility, European Molecular Biology Laboratory, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0352-2547
  18. Josef Anrather

    Feil Family Brain and Mind Research Institute, Cornell University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Sebastian Weis

    Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3201-2375
  20. Miguel P Soares

    Inflammation Laboratory, Instituto Gulbenkian de Ciência, Lisboa, Portugal
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9314-4833
  21. Arie Geerlof

    Institute of Structural Biology, Helmholtz Zentrum München, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  22. Jacques Neefjes

    Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6763-2211
  23. Michael Sattler

    Department of Chemistry, Technical University of Munich, Garching, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1594-0527
  24. Ana C Messias

    Institute of Structural Biology, Helmholtz Zentrum München, Munich, Germany
    For correspondence
    ana.messias@helmholtz-muenchen.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5449-9922
  25. Ana Neves Costa

    Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
    For correspondence
    arcosta@igc.gulbenkian.pt
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6506-7829
  26. Luis F Moita

    Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
    For correspondence
    lferreiramoita@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0707-315X

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.

Reviewing Editor

  1. Yousef Abu-Amer, Washington University Medical Center, United States

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).

Version history

  1. Preprint posted: April 29, 2020 (view preprint)
  2. Received: January 31, 2022
  3. Accepted: November 29, 2022
  4. Accepted Manuscript published: December 7, 2022 (version 1)
  5. Version of Record published: December 21, 2022 (version 2)

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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  1. Angelo Ferreira Chora
  2. Dora Pedroso
  3. Eleni Kyriakou
  4. Nadja Pejanovic
  5. Henrique Colaço
  6. Raffaella Gozzelino
  7. André Barros
  8. Katharina Willmann
  9. Tiago R Velho
  10. Catarina Moita
  11. Isa Santos
  12. Pedro Pereira
  13. Silvia Carvalho
  14. Filipa Batalha Martins
  15. João A Ferreira
  16. Sérgio Fernandes de Almeida
  17. Vladimir Benes
  18. Josef Anrather
  19. Sebastian Weis
  20. Miguel P Soares
  21. Arie Geerlof
  22. Jacques Neefjes
  23. Michael Sattler
  24. Ana C Messias
  25. Ana Neves Costa
  26. Luis F Moita
(2022)
DNA damage independent inhibition of NF-kB transcription by anthracyclines
eLife 11:e77443.
https://doi.org/10.7554/eLife.77443

Share this article

https://doi.org/10.7554/eLife.77443

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