Mitoxantrone induced impediment of histone acetylation and structural flexibility of the protein.
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.
Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202002, India.
Shahper N
SN
Khan
Ragothaman
R
Yennamalli
Naidu
N
Subbarao
Asad U
AU
Khan
D000107:Acetylation; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D002942:Circular Dichroism; D031541:Fluorescence Resonance Energy Transfer; D051548:Histone Acetyltransferases / Q000378:metabolism; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008942:Mitoxantrone / Q000737:chemistry* / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet; D013816:Thermodynamics
D000970:Antineoplastic Agents; D002843:Chromatin; D006657:Histones; D008942:Mitoxantrone; D051548:Histone Acetyltransferases