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

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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 104. 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.

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Acknowledgments

We are thankful to the central instrumentation facility (CIF) of IBU. This work was supported by the CSIR sanction no. 37(1209)04 EMR II. Author is also grateful to Prof Alok Bhattacharya, JNU, New Delhi for his support and critical discussion.

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Author notes

  1. Shahper N. Khan

    Present address: Translational Hematology and Oncology Research, Taussig Cancer Centre, Cleveland Clinic, Cleveland, OH, 44195, USA

  2. Ragothaman Yennamalli

    Present address: Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA, 50011, USA

Authors and Affiliations

  1. Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, 202002, India

    Shahper N. Khan & Asad U. Khan

  2. Centre for Computational Biology and Bioinformatics, Jawaharlal Nehru University, New Delhi, 110067, India

    Ragothaman Yennamalli & Naidu Subbarao

Authors
  1. Shahper N. Khan
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  4. Asad U. Khan
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Corresponding author

Correspondence to Asad U. Khan.

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Representative Coomassie gel for histone extraction from HEK293 cells (JPEG 20 kb)

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Khan, S.N., Yennamalli, R., Subbarao, N. et al. Mitoxantrone Induced Impediment of Histone Acetylation and Structural Flexibility of the Protein. Cell Biochem Biophys 60, 209–218 (2011). https://doi.org/10.1007/s12013-010-9141-9

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  • DOI: https://doi.org/10.1007/s12013-010-9141-9

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