Inhibition of N-Terminal Lysines Acetylation and Transcription Factor Assembly by Epirubicin Induced Deranged Cell Homeostasis

Abstract

Epirubicin (EPI), an anthracycline antitumour antibiotic, is a known intercalating and DNA damaging agent. Here, we study the molecular interaction of EPI with histones and other cellular targets. EPI binding with histone core protein was predicted with spectroscopic and computational techniques. The molecular distance r, between donor (histone H3) and acceptor (EPI) was estimated using Förster’s theory of non-radiation energy transfer and the detailed binding phenomenon is expounded. Interestingly, the concentration dependent reduction in the acetylated states of histone H3 K9/K14 was observed suggesting more repressed chromatin state on EPI treatment. Its binding site near N-terminal lysines is further characterized by thermodynamic determinants and molecular docking studies. Specific DNA binding and inhibition of transcription factor (Tf)-DNA complex formation implicates EPI induced transcriptional inhibition. EPI also showed significant cell cycle arrest in drug treated cells. Chromatin fragmentation and loss of membrane integrity in EPI treated cells is suggestive of their commitment to cell death. This study provides an analysis of nucleosome dynamics during EPI treatment and provides a novel insight into its action.

Histone Deacetylase Regulation of ATM-Mediated DNA Damage Signaling

“…The acetylation of histone H4 induced by vorinsotat was strongly inhibited by the addition of epirubicin (Figure 1D). This is likely due to inhibition of N-terminal lysine acetylation caused by binding of epirubicin to histone proteins (32). …”

Vinorelbine and epirubicin share common features with polysialic acid and modulate neuronal and glial functions

“…), and epirubicin binds to histone H3 (Khan et al . ). Furthermore, vinorelbine and epirubicin induce similar cellular responses as colominic acid in cell culture.…”

“…These small organic compounds can adopt a conformation that is compatible with the structure of PSA, as shown by modeling of PSA and epirubicin or vinorelbine into the antigen-binding pocket of antibody 735. That PSA, vinorelbine, and epirubicin can adopt similar conformations and thus may bind to the same cellular receptors is strengthened by the fact that all bind to histones: PSA binds to extracellularly localized histone H1 (Mishra et al 2010), vinorelbine binds to several histones (Rabbani-Chadegani et al 2009), and epirubicin binds to histone H3 (Khan et al 2012). Furthermore, vinorelbine and epirubicin induce similar cellular responses as colominic acid in cell culture.…”

Transcriptional Suppression of the NLRP3 Inflammasome and Cytokine Release in Primary Macrophages by Low-Dose Anthracyclines

“…Transcriptome analysis revealed a global transcriptional suppression of LPS-dependent genes in response to epirubicin. Epirubicin intercalates into DNA, and was found to inhibit the binding of transcription factors to DNA [27]. Although epirubicin binds to G-C sequences with higher affinity [27], it is not known whether epirubicin targets specific DNA sequences.…”

“…As epirubicin intercalates into DNA and inhibits transcription factor binding, resulting in attenuated regulation of RNA transcription [27], we hypothesized that the anti-inflammatory effect of epirubicin is due to reduced transcription regulatory capability. To test this hypothesis, we first analyzed the global effect on transcription by comparing the expression values of all expressed array genes in the absence or presence of epirubicin.…”