Interaction of anthracycline antibiotics with biopolymers. VIII. binding parameters of aclacinomycin A to DNA.

Katenkamp, Ulrich; Stutter, E.; Petri, I.; Gollmick, Friedrich A.; Berg, Hermann

doi:10.7164/antibiotics.36.1222

Cited by 14 publications

(6 citation statements)

References 22 publications

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“…Using isothermal titration calorimetry (ITC), we determined that two molecules of Epi or Acla bind to the DNA duplex with equilibrium dissociation constants ( K D ) of 11.4 and 11.7 μM, respectively ( Table 1 and Figure 4—figure supplement 1A, B ), indicating that Acla and Epi bind to the κB-33-derived DNA sequence with similar affinity. The affinity of Acla to different DNA molecules has been reported to be in the low nM to low µM range ( Furusawa et al, 2016 ; Skovsgaard, 1987 ; Utsuno and Tsuboi, 1997 ), while Doxo, which differs from Epi in the stereochemistry of the 4′-OH group, binds to DNA in the nM range ( Katenkamp et al, 1983 ). Most of the anthracyclines have a preference for GC- or TG-rich sequences, with the aglycon chromophore of the anthracyclines intercalating at a pyrimidine–purine step, and the sugar part interacting with the DNA minor groove ( Chaires, 2015 ; Frederick et al, 1990 ; Temperini et al, 2003 ).…”

Section: Resultsmentioning

confidence: 99%

DNA damage independent inhibition of NF-κB transcription by anthracyclines

Chora

Pedroso

Kyriakou

et al. 2022

eLife

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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.

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Section: Resultsmentioning

confidence: 99%

DNA damage independent inhibition of NF-κB transcription by anthracyclines

Chora

Pedroso

Kyriakou

et al. 2022

eLife

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“…Acla binds slightly stronger to DNA than Epi. In the literature, the affinity of Acla to different DNA molecules has been reported to be in the low nM to low µM range [36][37][38] , whilst compounds similar to Epi, like Doxo, that differs from Epi in the stereochemistry of the 4'-OH group, binds to DNA in the nM range 39 . It is known that most of the anthracyclines have a preference for GC-rich sequences.…”

Section: Epirubicin and Aclarubicin Disturb Rela-dna Bindingmentioning

confidence: 99%

“…5A, B), indicating that Acla and Epi bind to the κB-33-derived DNA sequence with similar affinity. The affinity of Acla to different DNA molecules has been reported to be in the low nM to low µM range (Furusawa et al, 2016;Skovsgaard, 1987;Utsuno and Tsuboi, 1997), whilst Doxo, which differs from Epi in the stereochemistry of the 4'-OH group, binds to DNA in the nM range (Katenkamp et al, 1983). Most of the anthracyclines have a preference for GC-rich or TG-rich sequences, with the aglycon chromophore of the anthracyclines intercalating at a pyrimidine-purine step, and the sugar part interacting with the DNA minor groove (Chaires, 2015;Frederick et al, 1990;Temperini et al, 2003).…”

Section: Epirubicin and Aclarubicin Bind To A κB-33 Promoter Sequencementioning

confidence: 99%

DNA damage independent inhibition of NF-κB transcription by anthracyclines

Chora

Pedroso

Pejanovic

et al. 2020

Preprint

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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-kB) 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-kB 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-kB subunit RelA and its DNA binding sites, to limit NF-kB-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 immunemediated inflammatory diseases. The nuclear factor kappa B (NF-kB) family of transcription factors, comprising RelA, RelB, c-Rel, p100 and p105, plays a prominent role in regulating inflammation 2 . All members share the N-terminal REL-homology domain (RHD) responsible for IkB binding, nuclear localization, dimerization and DNA binding. On their C-terminal region, RelA, RelB and c-Rel contain a transactivation domain (TAD), responsible for their transcriptional activity 3 . While NF-kB activation is strictly required to trigger the inflammatory response, uncontrolled NF-kB activity can result in a failure to resolve inflammation, contributing to the establishment of a growing number of pathological conditions 4 . At steady state, transcriptionally active NF-kB family members, of which RelA is the most abundant, are retained in the cytoplasm by their interaction with inhibitors of kB (IkB) molecules. IkBa phosphorylation in response to a variety of stimuli leads to its proteosomal degradation, a step required for RelA nuclear localization, DNA binding and initiation of gene transcription 5 3 . RelA-dependent IkBa re-synthesis is essential for its nuclear eviction and the timely termination of NF-kB transcriptional activity 6 7 . Posttranslational modifications within both RHD and TAD add an additional layer of control over RelA-dependent gene transcription, activating or repressing its transcriptional activity by controlling RelA association with IkB, nuclear localization, interaction with transcriptional cofactors, D...

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“…Anthracyclines are important antitumor antibiotics described in the monograph [43], including a chapter on DNA interaction. Equilibrium, kinetic, structural and polarographic data are summarized in [44,45,46]. Their structures consist of an anthraquinone derivative coupled with on, two or three ainosugars according to the general formula (III) with the exception of 5-Iminodaunomycin.…”

Section: Influence Of Ionic Strength On the Adsorption Behavior Of Domentioning

confidence: 99%

Selected Contributions to Polarography by the Bioelectrochemistry Laboratory at Jena

Berg

2003

Review of Polarography

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Interaction of anthracycline antibiotics with biopolymers. VIII. binding parameters of aclacinomycin A to DNA.

Abstract: The binding of aclacinomycin A to DNA was investigated spectrophotometrically under

Cited by 14 publications

References 22 publications

DNA damage independent inhibition of NF-κB transcription by anthracyclines

DNA damage independent inhibition of NF-κB transcription by anthracyclines

DNA damage independent inhibition of NF-κB transcription by anthracyclines

Selected Contributions to Polarography by the Bioelectrochemistry Laboratory at Jena

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