2. Academic Validation
  3. DNA damage independent inhibition of NF-κB transcription by anthracyclines

DNA damage independent inhibition of NF-κB transcription by anthracyclines

  • Elife. 2022 Dec 7:11:e77443. doi: 10.7554/eLife.77443.
Angelo Ferreira Chora # 1,  Dora Pedroso # 2,  Eleni Kyriakou 3 4,  Nadja Pejanovic 1,  Henrique Colaço 2,  Raffaella Gozzelino 5,  André Barros 2,  Katharina Willmann 2,  Tiago Velho 2 6,  Catarina F Moita 2,  Isa Santos 2 7,  Pedro Pereira 1,  Silvia Carvalho 1,  Filipa Batalha Martins 1,  João A Ferreira 1,  Sérgio Fernandes de Almeida 1,  Vladimir Benes 8,  Josef Anrather 9,  Sebastian Weis 10 11 12,  Miguel P Soares 13,  Arie Geerlof 3,  Jacques Neefjes 14,  Michael Sattler 3 4,  Ana C Messias 3 4,  Ana Neves-Costa 2,  Luis Ferreira Moita 2 15
Affiliations

Affiliations

  • 1 Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
  • 2 Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal.
  • 3 Institute of Structural Biology, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München, Neuherberg, Germany.
  • 4 Bavarian NMR Centre, Department of Bioscience, School of Natural Sciences, Technical University of Munich, Garching, Germany.
  • 5 NOVA Medical School (NMS), Lisbon, Portugal.
  • 6 Centro Hospitalar Lisboa Norte - Hospital de Santa Maria, EPE, Avenida Professor Egas Moniz, Lisbon, Portugal.
  • 7 Serviço de Cirurgia, Centro Hospitalar de Setúbal, Setúbal, Portugal.
  • 8 EMBL Genomics Core Facilities, Heidelberg, Germany.
  • 9 Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States.
  • 10 Institute for Infectious Disease and Infection Control, Friedrich-Schiller University, Jena, Germany.
  • 11 Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Friedrich-Schiller University, Jena, Germany.
  • 12 Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (HKI), Jena, Germany.
  • 13 Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal.
  • 14 Department of Cell and Chemical Biology, LUMC, Leiden, Netherlands.
  • 15 Instituto de Histologia e Biologia do Desenvolvimento, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
  • # Contributed equally.
PMID: 36476511 DOI: 10.7554/eLife.77443
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-κB 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.

Keywords

DNA damage response; anthracyclines; cancer; immunology; inflammation; mouse.

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