DNA damage independent inhibition of NF-κB transcription by anthracyclines

被引:11
作者
Chora, Angelo Ferreira [1 ]
Pedroso, Dora [2 ]
Kyriakou, Eleni [3 ,4 ]
Pejanovic, Nadja [1 ]
Colaco, Henrique [2 ]
Gozzelino, Raffaella [5 ]
Barros, Andre [2 ]
Willmann, Katharina [2 ]
Velho, Tiago [2 ,6 ]
Moita, Catarina F. [2 ]
Santos, Isa [2 ,7 ]
Pereira, Pedro [1 ]
Carvalho, Silvia [1 ]
Martins, Filipa Batalha [1 ]
Ferreira, Joao A. [1 ]
de Almeida, Sergio Fernandes [1 ]
Benes, Vladimir [8 ]
Anrather, Josef [9 ]
Weis, Sebastian [10 ,11 ,12 ]
Soares, Miguel P. [13 ]
Geerlof, Arie [3 ]
Neefjes, Jacques [14 ]
Sattler, Michael [3 ,4 ]
Messias, Ana C. [3 ,4 ]
Neves-Costa, Ana [2 ]
Moita, Luis Ferreira [2 ,15 ]
Abu-Amer, Yousef
机构
[1] Univ Lisbon, Fac Med, Inst Med Mol, Lisbon, Portugal
[2] Inst Gulbenkian Ciencias, Innate Immun & Inflammat Lab, Oeiras, Portugal
[3] Helmholtz Zentrum Munchen, Inst Struct Biol, Mol Targets & Therapeut Ctr, Neuherberg, Germany
[4] Tech Univ Munich, Bavarian NMR Ctr, Sch Nat Sci, Dept Biosci, Garching, Germany
[5] NOVA Med Sch NMS, Lisbon, Portugal
[6] EPE, Hosp St Maria, Ctr Hosp Lisboa Norte, Ave Prof Egas Moniz, Lisbon, Portugal
[7] Ctr Hosp Setubal, Serv Cirurgia, Setubal, Portugal
[8] EMBL Genom Core Facil, Heidelberg, Germany
[9] Weill Cornell Med, Feil Family Brain & Mind Res Inst, New York, NY USA
[10] Friedrich Schiller Univ, Inst Infect Dis & Infect Control, Jena, Germany
[11] Friedrich Schiller Univ, Jena Univ Hosp, Dept Anesthesiol & Intens Care Med, Jena, Germany
[12] Hans Knoll Inst HKI, Leibniz Inst Nat Prod Res & Infect Biol, Jena, Germany
[13] Inst Gulbenkian Ciencias, Inflammat Lab, Oeiras, Portugal
[14] LUMC, Dept Cell & Chem Biol, Leiden, Netherlands
[15] Univ Lisbon, Inst Histol & Biol Desenvolvimento, Fac Med, Lisbon, Portugal
基金
欧盟地平线“2020”; 欧洲研究理事会;
关键词
anthracyclines; cancer; inflammation; DNA damage response; Mouse; INDUCED APOPTOSIS; RELA HOMODIMER; BINDING; EXPRESSION; ATM; PHOSPHORYLATION; DOXORUBICIN; ACTIVATION; STRAND; DRUGS;
D O I
10.7554/eLife.77443
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-kappa B)-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-kappa B 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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页数:26
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