DNA damage independent inhibition of NF-kB transcription by anthracyclines.
Angelo Ferreira ChoraDora PedrosoEleni KyriakouNadja PejanovicHenrique G ColaçoRaffaella GozzelinoAndré BarrosKatharina WillmannTiago R VelhoCatarina MoitaIsa SantosPedro PereiraSilvia CarvalhoFilipa Batalha MartinsJoão A FerreiraSérgio Fernandes de AlmeidaVladimir BenesJosef AnratherSebastian WeisMiguel Parreira SoaresArie GeerlofJacques J C NeefjesMichael SattlerAna C MessiasAna Neves CostaLuis Ferreira MoitaPublished in: eLife (2022)
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-kB 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.
Keyphrases
- cell proliferation
- nuclear factor
- dna damage
- oxidative stress
- toll like receptor
- pi k akt
- early breast cancer
- dna repair
- genome wide
- circulating tumor
- cancer therapy
- anti inflammatory drugs
- copy number
- single molecule
- drug delivery
- cell free
- transcription factor
- signaling pathway
- lps induced
- multidrug resistant
- magnetic resonance
- intensive care unit
- genome wide identification
- acute kidney injury
- immune response
- nucleic acid
- high resolution
- nitric oxide
- dendritic cells
- stem cells
- mesenchymal stem cells
- nitric oxide synthase
- bone marrow
- protein kinase
- replacement therapy