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

TitleDNA damage independent inhibition of NF-κB transcription by anthracyclines.
Publication TypeJournal Article
Year of Publication2022
AuthorsChora AFerreira, Pedroso D, Kyriakou E, Pejanovic N, Colaço H, Gozzelino R, Barros A, Willmann K, Velho T, Moita CF, Santos I, Pereira P, Carvalho S, Martins FBatalha, Ferreira JA, de Almeida SFernandes, Benes V, Anrather J, Weis S, Soares MP, Geerlof A, Neefjes J, Sattler M, Messias AC, Neves-Costa A, Moita LFerreira
Date Published2022 Dec 07
KeywordsAnimals, Anthracyclines, Antibiotics, Antineoplastic, DNA, DNA Damage, Doxorubicin, Mice, NF-kappa B

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.

Alternate JournalElife
PubMed ID36476511
PubMed Central IDPMC9771368