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

DOI
https://doi.org/10.7554/eLife.77443
Journal volume & issue
Vol. 11

Abstract

Read online

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.

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