Author(s):
Chora, Angelo Ferreira ; Pedroso, Dora ; Kyriakou, Eleni ; Pejanovic, Nadja ; Colaço, Henrique ; Gozzelino, Raffaella ; Barros, André ; Willmann, Katharina ; Velho, Tiago ; Moita, Catarina F. ; Santos, Isa ; Pereira, Pedro ; Carvalho, Silvia ; Martins, Filipa Batalha ; Ferreira, João A. ; de Almeida, Sérgio Fernandes ; Benes, Vladimir ; Anrather, Josef ; Weis, Sebastian ; Soares, Miguel P. ; Geerlof, Arie ; Neefjes, Jacques ; Sattler, Michael ; Messias, Ana C. ; Neves-Costa, Ana ; Moita, Luis Ferreira
Date: 2022
Persistent ID: http://hdl.handle.net/10362/147238
Origin: Repositório Institucional da UNL
Subject(s): anthracyclines; cancer; DNA damage response; immunology; inflammation; mouse; Neuroscience(all); Biochemistry, Genetics and Molecular Biology(all); Immunology and Microbiology(all); SDG 3 - Good Health and Well-being
Description
Funding: We are grateful to the Genomics Unit, Bioinformatics, and the Animal House at IGC. We thank Margarida Gama-Carvalho for the critical revision of the manuscript. This work was supported by the European Commission Horizon 2020 (ERC-2014-CoG 647888-iPROTECTION) and by Fundação para a Ciência e Tecnologia (FCT: PTDC/BIM-MEC/4665/2014 and EXPL/MED-IMU/0620/2021). SW is funded by the Deutsche Forschungsgemeinschaft, DFG, project number WE 4971/6-1, the Excellence Cluster Balance of the Microverse (EXC 2051; 390713860), and the Federal Ministry of Education and Research (BMBF) project number 01EN2001.
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.
