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.
Highlights
The pharmacological treatment of cancer is often still unsuccessful
The interaction of antitumour drugs with chromatin has been the subject of many reports, which have consistently shown the binding of these drugs to chromatin [23,24]
Chromatin consists of DNA, histones and a plethora of different protein complexes that assist with the dynamic changes occurring during DNA replication, cell-cycle progression, regulated-transcriptional and posttranscriptional events, DNA repair and recombination
Summary
The pharmacological treatment of cancer is often still unsuccessful. This is mainly due to the lack of discovery of new effective anticancer drugs, the severe side effects associated with conventional chemotherapy and the possibility of multidrug resistance, often induced by cytotoxic agent administration. Innovative ideas and new strategies are needed in order to overcome these obstacles and to obtain the selective destruction of neoplastic cells To this aim, optimal insights into the mechanisms of action at subcellular and molecular levels of antitumoural action and identification of their cellular targets constitute indispensable stages. Some recent studies have shown that covalently binding agents disrupt the binding of transcription factors to their specific consensus sequences [1] The ability of these adducts to prevent Tf-DNA binding in tumor cells infer that the sequence selectivity of a drug will determine which transcription factors are affected, and which genes are inhibited. One possible physiological action of these drugs in tumor cells may involve the altered pattern of histone modification, histone acetylation which is supposed to play a crucial role in cellular proliferation and differentiation
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