Mitoxantrone Induced Impediment of Histone Acetylation and Structural Flexibility of the Protein

Abstract

Mitoxantrone (MTX), a choice of drug in cancer chemotherapeutic regime, is a potent and less toxic among anthracycline class of drugs. Here, we study the molecular interaction of MTX, with histone and its acetylation dynamics. Its binding with histone core protein was predicted with CD and UV-visible spectroscopic techniques. The MTX-protein complex resulted in the impediment of the histone acetyltransferase (HAT) activity in a dose dependent manner on MTX binding. Interestingly, the concentration dependent reduction in acetylated state of specific lysines K9/K14 was also observed on MTX treatment in vivo. The molecular distance r, between donor (histone H3) and acceptor (MTX) was estimated using Förster's theory of non-radiation energy transfer and the detailed binding phenomenon was expounded. MTX binding site near N-terminal lysines is characterized with an association constant of the order of 10(4). The positive thermodynamic values of both ∆H° and ∆S° were suggestive that the hydrophobic interactions dominate in MTX-protein binding. The binding site allocation predicted by computational modeling placed the drug molecule near N-terminal lysine K9 and K14 of histone H3, and corroborate with the thermodynamic interaction model. The study establishes that MTX-histone interaction affects protein acetylation state and also provided a mechanistic model for its binding. Hence, MTX interaction may affect chromatin structure and implicates its role in transcriptional regulation at epigenetic level.

The DNA intercalators ethidium bromide and propidium iodide also bind to core histones

“…In the above set of experiments we have shown that the DNA intercalators, PI and EB, interact with core histones. This interaction could potentially alter post‐translational modification of core histones, such as acetylation as had been reported in case of mitoxantrone [10] and was therefore explored ex vivo . Significantly, PI and EB could alter global acetylation status of histone H3 and H4.…”

“…The former class of ligands binds to chromosomal DNA only while the later has the ability to bind both histone(s) and chromosomal DNA. Studies from our laboratory and others had shown that the plant alkaloid sanguinarine [7], daunomycin and mitoxantrone [8,9] interact with both DNA and core histones and affect post-translational modifications like histone acetylation [10].…”

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

“…Forster theory predicted the close proximity and the non-radiation energy transfer between EPI and Histones [26]. Furthermore, reduction in the histone H3 K9/K14 acetylation (Figure 3) shows the drug induced inhibition of acetylation.…”

Oxidative Stress Induced Functional and Structural Modifications of High Molecular Mass Goat Brain Cystatin

“…They are known to generate singlet oxygen, hydroxyl radicals and flavin triplet state on photoillumination. Generated H 2 O 2 may modify *Address correspondence to this author at the Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh -202002, India; Tel: +91-571-2700857; Fax: +91-571-2702758; E-mail: bilqees2007@gmail.com amino acids [18], degrade heme in red blood cells [19] and inactivate enzymes [20] and antiproteinase [21,22]. Its concentration may markedly increase when tissues are exposed to ionizing radiations during metabolism of carcinogens and at inflammatory sites [17,18].…”