RT Journal Article
SR Electronic
T1 DNA damage independent inhibition of NF-κB transcription by anthracyclines
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.27.065003
DO 10.1101/2020.04.27.065003
A1 Angelo Chora
A1 Dora Pedroso
A1 Nadja Pejanovic
A1 Eleni Kyriakou
A1 Henrique Colaço
A1 Raffaella Gozzelino
A1 André Barros
A1 Katharina Willmann
A1 Tiago Velho
A1 Catarina F. Moita
A1 Isa Santos
A1 Pedro Pereira
A1 Sílvia Carvalho
A1 Filipa Martins
A1 João A. Ferreira
A1 Sérgio Fernandes de Almeida
A1 Vladimir Benes
A1 Josef Anrather
A1 Miguel P. Soares
A1 Arie Geerlof
A1 Jacques Neefjes
A1 Michael Sattler
A1 Ana C. Messias
A1 Ana Neves-Costa
A1 Luís Ferreira Moita
YR 2020
UL http://biorxiv.org/content/early/2020/04/29/2020.04.27.065003.abstract
AB Transcriptional programs leading to induction of a large number of genes can be rapidly initiated by the activation of only few selected transcription factors. Upon stimulation of macrophages with microbial-associated molecular patterns (MAMPs), the activation of the nuclear factor kappa B (NF-κB) family of transcription factors triggers inflammatory responses that, left uncontrolled, can lead to excessive inflammation with life-threatening consequences for the host. Here we identify and characterize a novel effect of Anthracyclines, a class of drugs currently used as potent anticancer drugs, in the regulation of NF-κB transcriptional activity in BMDMs, in addition to the previously reported DNA damage and histone eviction. Anthracyclines, including Doxorubicin, Daunorubicin and Epirubicin, disturb the complexes formed between the NF-κB subunit RelA and its DNA binding sites, to limit NF-κB-dependent gene transcription during inflammatory responses, including of pivotal pro-inflammatory mediators such as TNF. We observed that suppression of inflammation can also be mediated by Aclarubicin, Doxorubicinone and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other Anthracyclines, but do not induce DNA damage in the tested concentrations. This novel mechanism of action of Anthracyclines, contributing to the reduction of inflammation, is thus independent of the activation of DNA damage responses and may be relevant for the development of novel strategies targeting immune-mediated inflammatory diseases.Competing Interest StatementThe authors have declared no competing interest.