eLife (Dec 2022)
DNA damage independent inhibition of NF-κB transcription by anthracyclines
- Angelo Ferreira Chora,
- Dora Pedroso,
- Eleni Kyriakou,
- Nadja Pejanovic,
- Henrique Colaço,
- Raffaella Gozzelino,
- André Barros,
- Katharina Willmann,
- Tiago Velho,
- Catarina F Moita,
- Isa Santos,
- Pedro Pereira,
- 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 Ferreira Moita
Affiliations
- Angelo Ferreira Chora
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Dora Pedroso
- ORCiD
- Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
- Eleni Kyriakou
- Institute of Structural Biology, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München, Neuherberg, Germany; Bavarian NMR Centre, Department of Bioscience, School of Natural Sciences, Technical University of Munich, Garching, Germany
- Nadja Pejanovic
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Henrique Colaço
- ORCiD
- Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
- Raffaella Gozzelino
- NOVA Medical School (NMS), Lisbon, Portugal
- André Barros
- Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
- Katharina Willmann
- Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
- Tiago Velho
- ORCiD
- Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal; Centro Hospitalar Lisboa Norte - Hospital de Santa Maria, EPE, Avenida Professor Egas Moniz, Lisbon, Portugal
- Catarina F Moita
- ORCiD
- Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
- Isa Santos
- Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal; Serviço de Cirurgia, Centro Hospitalar de Setúbal, Setúbal, Portugal
- Pedro Pereira
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Silvia Carvalho
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Filipa Batalha Martins
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- João A Ferreira
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Sérgio Fernandes de Almeida
- ORCiD
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Vladimir Benes
- ORCiD
- EMBL Genomics Core Facilities, Heidelberg, Germany
- Josef Anrather
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States
- Sebastian Weis
- ORCiD
- Institute for Infectious Disease and Infection Control, Friedrich-Schiller University, Jena, Germany; Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Friedrich-Schiller University, Jena, Germany; Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (HKI), Jena, Germany
- Miguel P Soares
- ORCiD
- Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
- Arie Geerlof
- Institute of Structural Biology, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München, Neuherberg, Germany
- Jacques Neefjes
- ORCiD
- Department of Cell and Chemical Biology, LUMC, Leiden, Netherlands
- Michael Sattler
- ORCiD
- Institute of Structural Biology, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München, Neuherberg, Germany; Bavarian NMR Centre, Department of Bioscience, School of Natural Sciences, Technical University of Munich, Garching, Germany
- Ana C Messias
- ORCiD
- Institute of Structural Biology, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München, Neuherberg, Germany; Bavarian NMR Centre, Department of Bioscience, School of Natural Sciences, Technical University of Munich, Garching, Germany
- Ana Neves-Costa
- ORCiD
- Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
- Luis Ferreira Moita
- ORCiD
- Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal; Instituto de Histologia e Biologia do Desenvolvimento, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
- DOI
- https://doi.org/10.7554/eLife.77443
- Journal volume & issue
-
Vol. 11
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