Portal de Periódicos da CAPES

DNA damage independent inhibition of NF-κB transcription by anthracyclines

2022; eLife Sciences Publications Ltd; Volume: 11; Linguagem: Inglês

10.7554/elife.77443

2050-084X

Ângelo Ferreira Chora, Dora Pedroso, Eleni Kyriakou, Nadja Pejanovic, Henrique G. Colaço, Raffaella Gozzelino, André Barros, Katharina Willmann, Tiago R. Velho, Catarina Moita, Isa Santos, Pedro Pereira, Sílvia Carvalho, Filipa Batalha Martins, João Ferreira, Sérgio F. de Almeida, Vladimı́r Beneš, Josef Anrather, Sebastian Weis, Miguel P. Soares, Arie Geerlof, Jacques Neefjes, Michael Sattler, Ana C. Messias, Ana Neves‐Costa, Luís F. Moita,

Natural product bioactivities and synthesis

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.