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Chora, A.F.* ; Pedroso, D.* ; Kyriakou, E. ; Pejanovic, N.* ; Colaço, H.* ; Gozzelino, R.* ; Barros, A.* ; Willmann, K.* ; Velho, T.R.* ; Moita, C.* ; Santos, I.* ; Pereira, P.* ; Carvalho, S.* ; Martins, F.B.* ; Ferreira, J.A.* ; de Almeida, S.F.* ; Benes, V.* ; Anrather, J.* ; Weis, S.* ; Soares, M.P.* ; Geerlof, A. ; Neefjes, J.J.* ; Sattler, M.* ; Messias, A.C. ; Neves Costa, A.* ; Moita, L.F.*

DNA damage independent inhibition of NF-kB transcription by anthracyclines.

eLife 11:e77443 (2022)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Immunology ; Inflammation ; Mouse; Induced Apoptosis; Rela Homodimer; Binding; Expression; Atm; Phosphorylation; Doxorubicin; Activation; Strand; Drugs
ISSN (print) / ISBN 2050-084X
e-ISSN 2050-084X
Journal eLife
Quellenangaben Volume: 11, Issue: , Pages: , Article Number: e77443 Supplement: ,
Publisher eLife Sciences Publications
Publishing Place Sheraton House, Castle Park, Cambridge, Cb3 0ax, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
Grants European Research Council (ERC)
Fundacao para a Ciencia e a Tecnologia
H2020 European Research Council